Sciencemadness Discussion Board

theoretical amphetamine variants

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Cloner - 18-11-2006 at 05:19

The analogy between MDMA and methamphetamine and their variants makes me wonder about similar molecules that differ only in the aromatic system. I am working on pyrrolealdehydes, and it seems that a lot of reactions can be achieved analogous to benzenealdehydes. Has anyone looked at a methamphetamine like molecule that has a pyrrole ring (pyridine, furan, thiophene, naphtalene, etc) instead? Depending on the precise action of the molecule on the brain, such molecules might be potent in unexpected ways, such as lobotomizing/killing you in a very efficient manner, or be another variant drug:D

Nicodem - 19-11-2006 at 04:07

You need to be more specific. Are you looking for references to just any 1-(heteroaryl)isopropylamine or, like you insinuate in your first sentence, to monoamine releasing (heteroaryl)isopropylamines? Is it OK if they have other activity as well?
For example 1-(indol-3-yl)isopropylamine has 5-HT2A/2C agonism in addition to some slight MAO inhibitory action, but I don't know if its monoamine releasing ability was ever confirmed. Several of its ring substituted analogues are also well known for psychedelic activity.
Several 1-(indol-1-yl)isopropylamines were reported of being 5-HT2C agonists.
Several patents indicate that the equivalent indazol-3-yl and indazol-1-yl versions have 5-HT receptor affinity as well.
1-(thien-2-yl)isopropylamine is long known for its stimulant activity and recently its activity in men was described. The tester described it as equipotent to amphetamine by dose, but distinctively different. Several halogenated 1-(thien-2-yl)isopropylamines were also evaluated for their MAO inhibition and serotonin uptake inhibition.
Pyridin-3-yl and 6-methyl-pyridin-2-yl isopropylamines were prepared but their activity in rats remains unreported, probably due to inactivity. Same goes for the 1-(furan-2-yl)isopropylamine.
Interestingly, the 1-(heteroaryl)isopropylamines that have great potential for being mixed monoamine releasers were never reported to my knowledge. I'm talking about benzofuran-5-yl and benzofuran-6-yl isopropylamines, though their 2,3-dihydro versions were found to be monoamine releasers (serotonine mostly). And also the benzoxazol-5-yl and benzoxazol-6-yl, the indole and indazole, and the thio versions of these all. But then again given that even the most obvious choice for a mixed monoamine releaser, the 1-(naphth-2-yl)isopropylamine, remains unreported, it is no surprise there is little interest in the mentioned heteroaryl modifications.
There is also a rich spectrum of psychedelic 1-(heteroaryl)isopropylamines reported in literature. Most recently, the famous "dragonfly" compounds. But even previously there were reports of 1-(5-methoxybenzofuran-3-yl)isopropylamine and its 5-HT2A affinity. If I remember correctly, the thio counterpart was also evaluated. Surprisingly though, the 1-(indol-4-yl)isopropylamines were never evaluated even though it is apparent from the structure activity relationship that they would be potent psychedelics.
If you allow the amine side chain to be the ethylamine and N-alkylated ethylamine then the spectrum of researched 2-(heteroaryl)ethylamines becomes really wide including mostly indol-3-yl derivatives, but also many others like benzimidazoles and even rare heteroaromatics like thienopyrroles, for example.

PS: References on demand. I don't have the time to compile all of them.

Edit: I have not seen references for 1-(pyrrol-2-yl)isopropylamine yet.

[Edited on 19-11-2006 by Nicodem]

Cloner - 19-11-2006 at 05:26

Interesting. The question is whether it is due to difficulty in synthesis that this has not been tried, or simply because its unlikely to work. If I understand correctly from your post (thanks a lot by the way) there is sometimes effect, sometimes not, hence a lot of potential.

What I am working at is the synthesis of functionalized heteroaromatics from aldehyde functionalities, and develop a high yielding procedure. Hence the interest in hive related science, because there is a plethora of techniques available that apply to aromatic aldehydes, with their differences well documented. This made me think of the analogous molecules of heteroaromatics or longer chain aromatic aldehydes (ie, a benzaldehyde with a methylpyrrole group on the para position and infinite variants thereon). It is a bit of my private project to apply this kind of thing to exotic isopropylamines, and I know next to nothing about clinical tests for molecules.

Sandmeyer - 19-11-2006 at 06:09

Aside from that you want to make 4-heteroaryl substituted amphetamines starting from benzaldehyde, your post makes no sence at all to me. "Plethora of techniques available" - like what and for what?

Cloner - 19-11-2006 at 07:01

I mean that the amphetamine boys have investigated dozens of methods for aldehyde chemistry, and that the hive is a better resource than any textbook on this specific topic.

Sandmeyer - 19-11-2006 at 07:53

Sounds groovy, go for it!

Nicodem - 19-11-2006 at 07:54

So you are not interested in heteroarylisopropylamines? I wrote my review for nothing? Cloner, next time state your questions clearly and properly! I can't read minds.
As for the 4-heteroaryl-amphetamines, I have no knowledge. But in order to avoid further confusion, please state precisely whether you mean 4-heteroaryl-amphetamines, 4-heteroarylalkyl-amphetamines or amphetamine ring-condensed with heteroaromatics. (use a graphic representation if you can't use IUPAC)
State also what kind of activity (or pharmacodynamics) you want: stimulant (DA/NE releasers), emphatogenic (mixed monoamine releasers), psychedelic (5-HT2A agonists), narcotic (mu agonistic) and so on.
Without properly phrasing the question you can not get a proper answer. Or else the answer can just as well be "42".
Quote:
Interesting. The question is whether it is due to difficulty in synthesis that this has not been tried, or simply because its unlikely to work. If I understand correctly from your post (thanks a lot by the way) there is sometimes effect, sometimes not, hence a lot of potential.


What do you mean? In my reply I described that there was done A LOT on heteroarylisopropylamines and even much more on the heteroarylethylamines of various types of activity. There is even MUCH MORE that can still be done. The difficulty of synthesis has nothing to do with it. For example, 1-(naphtha-2-yl)isopropylamine is very easy to prepare and it would be expected to have empatogenic activity, yet there is nothing on its pharmacology in the literature. The same goes for the heteroarylisopropylamines, for example 1-(benzofuran-6-yl)isopropylamine is well worth researching yet it is not researched. This has nothing to do with synthesis but it has a lot to do with the fact that there are only a couple of labs in the world developing new monoamine releasers and they can't do everything. They have lots of other great ideas to check out first. As for the amateur researchers, it is well known that, even if they are not just methheads, they are nevertheless mostly just a bunch of lazy bastards that can't get their attention span a minute away from the well known and appraised, long time ago discovered psychoactive compounds.

Drunkguy - 19-11-2006 at 08:15

When I was working on epibatidine type molecules at university, naturally I used to search engine to see if any heteroaryl-IPA analogs had been made. Although this was not the case, I did see that 3-pyridyl analog had been made and as such is active. I forget the details now although I recall that some work had been done in this area.

^To the above poster, the napthyl analog has been prepared recently by a researcher known as Rothman. There is a lonk to his work upon a request I made in the reference section. However it must be stressed that the compound acts primarily as a serotonergic and as such, is a cowboy drug and not expected to be a hit with the indians.

Here is the link to the article. As we can see, there is not really anything fantastic here.

[Edited on 19-11-2006 by Drunkguy]

Nicodem - 19-11-2006 at 08:35

Thanks a lot Drunkguy. :D That review rocks!

You are wrong though. According to that paper 1-(naphth-2-yl)isopropylamine is extremely cool no mater what the Indians and cowboys think. Its 5-HT/DA release ratio of 3.7 is just perfect. I went to check the 5-HT/DA release ratio for MDA (JMC, 36 (1993) 3700-6) and it is 3.7 exactly like our fellow naphthyl derivative! :) (though I used the IC50 ratio and not the release at the same concentration, but assuming linearity to some extent…)
But then there is also the NE to take into consideration and probably a bunch of other stuff. 1-(naphth-2-yl)isopropylamine might also have more than just negligible affinity to some 5-HT receptors.
Chances are that the 5-HT/DA release ratio could be slightly lowered by N-methylation for those who don't like to keep it that high. Though unfortunately on the account of the dose potency.

The paper also says that p-Me-amphetamine has a 5-HT/DA release ratio of 0.82 which explains why the guys who tasted it reported a kind of emphatogenic activity. I always suspected it was a mixed releaser. But it is interesting to se p-fluoroamphetamine having only negligible 5-HT releasing ability (just 11 times more than plain amphetamine). I expected a higher ratio for this compound. Too bad they did not also measure the ratio for p-nitroamphetamine that is supposed to be a very potent mixed monoamine releaser.

Edit: Rearranged the text to make more sense.

[Edited on 19-11-2006 by Nicodem]

Sandmeyer - 19-11-2006 at 13:31

Great piece of paper Drunkguy, highly interesting!

Cloner - 22-11-2006 at 04:03

Nicodem, this is a very wide topic and your answer made a lot of things very clear even if the question was halfway unspecified.

My focus of research is very limited. I cannot invent ten thousand different wheels at the same time, so this is why I am specifically poking into the sequence aldehyde -> nitropropene -> amphetamine and try to apply it to heteroaromats. Such a variant i could make in a short time on pyrrole, if that nitrogen in the ring wouldn't be such a bitch. Also it is very likely that someone has thought it before, hence this post. Nonetheless, there are other potentially interesting variants which are worth discussing even if I am not going into the lab to actually do it tomorrow.

ummm and drunkguy could you pm me the password on that forum, it seems mine is a year out of date:D

[Edited on 22-11-2006 by Cloner]

Nicodem - 22-11-2006 at 12:34

I would gladly give you more advices, but still I wander why you can't give such simple explanation as about what basic structure and what activity you want? (I don't read minds!)

Cloner - 23-11-2006 at 04:27

Consider amphetamine and keep only the side chain. Put another 6-ring or 5-ring or more complex ring in place of the benzene ring. What is the physiological effect of this molecule?

I admit I wrote this BEFORE thinking on it for a week, and I don't have the guts (or insanity) to try it out on myself and it'd end up on a shelf. However, I made dangerous stuff for the sake of making it before.


[Edited on 23-11-2006 by Cloner]

Chris The Great - 23-11-2006 at 04:39

Quote:
Originally posted by Nicodem
So you are not interested in heteroarylisopropylamines? I wrote my review for nothing?


I certainly found it interesting, and will probably come back to it in a while when I get the ability to do more advanced organic synthesis. All the compounds seemed unique and interesting, hence synthesis worthy.

Nicodem - 23-11-2006 at 12:14

Thanks Chris.
Quote:
Originally posted by Cloner
Consider amphetamine and keep only the side chain. Put another 6-ring or 5-ring or more complex ring in place of the benzene ring.

So, you are interested in the 1-(heteroaryl)isopropylamines like you insinuated in the first post? Then after I replied you wrote "ie, a benzaldehyde with a methylpyrrole group on the para position and infinite variants thereon" meaning that you were interested in 4-heteroarylamphetamines which are something completely different. Please be clear and concise and use IUPAC nomenclature when talking about structures!
Quote:
What is the physiological effect of this molecule?

Huh! Which molecule?
Quote:
I admit I wrote this BEFORE thinking on it for a week, and I don't have the guts (or insanity) to try it out on myself and it'd end up on a shelf. However, I made dangerous stuff for the sake of making it before.

What dangers are you talking about? These compounds are fully legal and their synthesis is nothing dangerous at all (unless you are completely ignorant and clumsy). They are legal even in countries with such shady and irrational laws like the USA's "Analogue act" unless you are some asshole that wants to sell surrogate drugs on the street in which case you would deserve all the danger and the consequences. As long as they are made for research purposes, most governments would even encourage you, at least that’s what they do with the academic researchers. ;)

turd - 23-11-2006 at 15:09

Quote:
Huh! Which molecule?

1-(Thiophen-2-yl)isopropylamine and 1-(thiophen-3-yl)isopropylamine sound like obvious candidates.

PS: When discussing articles it would be nice if you would post the reference.

Nicodem - 24-11-2006 at 00:24

Like I said, references are only on demand. I don't have the time to write full reviews, especially if I'm unsure that there is anybody interested, but I do have the time to give references for specific compounds when wanted.

1-(thien-2-yl)isopropylamine:

1-(thien-3-yl)isopropylamine:

I left out a couple of patents and obscure references. Otherwise this is about all I can find on these two compounds. Let me know if there is a paper you can not obtain. I have them all but the reference 14.

[Edited on 24-11-2006 by Nicodem]

Ephoton - 25-11-2006 at 20:54

I have heard that methyl groups on the benzene ring on an oxalone does not
destroy the euphoric effects of the compound.
what do you think about an indane ring instead.
this is just out of curiosity.

turd - 27-11-2006 at 12:32

Wow, that's what I call service. :o Thank you, Nicodem!
Quote:
I have them all but the reference 14.

Which one?

I was thinking about a simple way of making the 2-furyl analogue:
furfuryl alcohol --(SOCl2)--> (2-furyl)-chloromethane --(1. Mg, 2. MeCN, 3. NaBH4)--> (2-furyl)-IPA
Unfortunately the chloromethane seems to be very unstable and I have no PBr3 for making the bromide. :(

Alternatively one could make the (2-furyl)-acetonitrile and the grignard with MeMgI, but my KCN and my PTC are planned for another experiment.

grumble, grumble...

Nicodem - 27-11-2006 at 14:52

Quote:
Originally posted by turd
Quote:
I have them all but the reference 14.

Which one?


Sorry, that was a mistake after renumbering the references. I meant the reference 16.) Arzneimittel-Forschung, 12 (1962) 902-7. It should be in German and it discusses the pharmacological properties of various heteroarylisopropylamines.

1-(fur-2-yl)isopropylamine was also tested by Alles and Feigen (reference 1) and was found to be several times weaker than the thio analogoue in animals for most physiological activities and inactive in animal model of CNS stimulation (no locomotor effects in the same test where the thio analogue was active). Alles ingested 20mg and 50mg without effects. Feigen reported hints of stimulation at 20mg but then nothing at 50mg.

The furfuryl halogenides are all quite instable and I'm unsure they can be used in a Grignard reaction.

jon - 28-11-2006 at 15:48

by this compound (1-(thien-2-yl)isopropylamine) you imply thiophene substitution for benzene in say phenylisopropylamine?
I'm not too clear on the nomenclature.
thiophene rings follow huckel's rule?
on napthyl substituted isopropylamines they sound interesting i think you can try a direct synthetic approach where you could avoid formylation, henry condensation, and then reduction. say for exapmple you could go directly to ketone by conjugating acetone with it as in the p2p synthesis using Mn(III) acetate, acetone in acetic acid the napthyl-2-substitution is tantamount to the para position on the benzene ring right? because I think that process is para selective. (there is some confusion there too in one post it's listed 2-sub and the other it's 1-substituted) theres also other means involving organo zinc type reactions where you can tack on a methyl ketone to an aromatic ring and there's friedel crafts alkylation with chloro acetone (I would'nt recommend either because of the lacrymatory effects of halogented ketones might make this rather unpleasant process to deal with). you could do something similar with toulene to get the para methyl phenylisopropylamine you mention that has empathogenic properties. there's an abstract I read about 2,5 dimethyl amphetamine (you could use para xylene in this case) where it is said to have equivalent therapuetic value to amphetamine but less pressor side effects (high blood pressure, palpitations).
I could'nt access that article linked up there can someone help with this?
I curious if there has been human trials of the napthylisopropylamines. they sound like they have promise and avoid the legal implications of the analouge act.
another synthetic stategy involves friedel crafts alkylation of (whatever the aromatic is) with allylchloride and Fe(III)Cl this has the advantage that the allyl moiety will alkylate the ring and then the HCl produced by the reaction will add markovnikov to the double bond being catalyzed by the lewis acid. to give a direct intermediate(aryl-2-chloro-propane). you can then perform a finkelstein reaction on this with sodium iodide to get a 2-iodo intermediate which is the better leaving group.
I'm sure allyl bromide would be optimal for overall ease.
the problem in this scheme of course is multiple ring substitution, and reduced yeilds as a result.
oh and in the last post about benzofuranylisopropylamines, the thio analouge would be sulfur substitution in the furan ring correct?
in the case of thiphene-2-aldehydes as the proposed starting material to the thiophenepropan-2-ones would be aldol condensation with methylethyl ketone(catalysed by hydrogen chloride gas) and then oxidation of this to the propanone with performic acid (oxidation is a misnomer because hydrolysis also takes place)

[Edited on 28-11-2006 by jon]

[Edited on 28-11-2006 by jon]

[Edited on 29-11-2006 by jon]

[Edited on 29-11-2006 by jon]

[Edited on 29-11-2006 by jon]

[Edited on 29-11-2006 by jon]

turd - 1-12-2006 at 03:15

Quote:
by this compound (1-(thien-2-yl)isopropylamine) you imply thiophene substitution for benzene in say phenylisopropylamine?

Yes, a google search would have told you that in a few seconds.
Quote:
thiophene rings follow huckel's rule?

http://en.wikipedia.org/wiki/Aromaticity#Heterocyclics
Quote:
[...]

Interesting, but neither xylene nor naphthalene are heterocycles.
Quote:
oh and in the last post about benzofuranylisopropylamines, the thio analouge would be sulfur substitution in the furan ring correct?

I don't know which post, but yes, sounds correct.
Quote:
in the case of thiphene-2-aldehydes as the proposed starting material to the thiophenepropan-2-ones would be aldol condensation with methylethyl ketone(catalysed by hydrogen chloride gas) and then oxidation of this to the propanone with performic acid (oxidation is a misnomer because hydrolysis also takes place)

Mmh? Could you elaborate on that?
The aldehyde has 1 carbon in the side chain and MEK has 4. Even if you don't get a mess that makes a side chain with 5 carbon atoms, i.e. a pentane.

jon - 1-12-2006 at 22:58

a quick search on google yeilds many supplier's of thiophene-2-carboxaldehyde. available from ll over the world our slanty eyed friends are your best bet probably.
I can't find the reference right now I'll dig it up you get a methyl butene-ol via aldol condesation and baeyer-villiger oxidattion will give an ester derivative which will slpit off to a methyl ketone I'm sure of this.
It would be more convenient to catalylize the reaction with with sulfuric acid(in acetic acid) than to bubble hydrogen chloride gas into it, or on the surface it looks easier to do it this way.
ahh here it is!

Phenylacetone by Bayer-Villiger Oxidation of 2-acetyl-1-phenylprop-1-ene
Boeeseken & Jacobs
Recl. Trav. Chim. Pays-Bas 55, 786 (1936)

Peracetic acid treatment of 2-acetyl-propenylbenzene (3-methyl-4-phenyl-but-3-en-2-one) below 30°C resulted in the formation of phenylacetone enol acetate (2-acetoxy-1-phenylprop-1-ene), mp 131°C and bp 103°C/3mmHg. Heating the crude reaction mixture with aqueous HCl at 80°C gave phenylacetone.

For more information check the old Twodogs' thread from The Hive (post No 245942).
oh and not to split hairs where did I Imply napthyl rings were hetero cyclic? I only stated I was interested if there were any human reports of it's qualitative effects (the isopropylamines) It sure sounds tantalizing and best of all legal!

[Edited on 2-12-2006 by jon]

[Edited on 2-12-2006 by jon]

[Edited on 2-12-2006 by jon]

[Edited on 2-12-2006 by jon]

turd - 2-12-2006 at 08:29

I see... Baeyer-Villiger. That's a pretty clever synthesis strategy. I wonder if it works well - I'm a bit weary of pre-NMR and pre-GC/MS publications.

jon - 2-12-2006 at 13:33

I dunno ketones are pretty easy to characterize, without 1h-nmr or gc/ms it might be paydirt. it sure beats henry condensation it's easy to get mek, and hydrogenperoxide, and acetic or formic acid.
BTW would nicodem be so kind to translate that thread from hyperlab? I can't read cyrillic and I'm dying to know the subjective on the thiophene analog.
In what way is it distintly different from amphetamine?
here's where I'm confused gordon alles says it's equipotent to amphetamine in dogs yet tries it himself and reports no cns activity.

[Edited on 2-12-2006 by jon]

garage chemist - 2-12-2006 at 14:37

I propose a theoretical synthesis of 2-naphthylisopropylamine:

- sulfonation of naphthalene with conc. H2SO4 at 160- 170°C (at lower temperatures the 1-sulfonic acid is preferred, at higher temps the 2-sulfonic acid) to naphthalene 2-sulfonic acid

-fusion of potassium 2-naphthalenesulphonate with potassium cyanide to make 2-naphthonitrile (I do not know if this works)

- conversion to 2-naphthaldehyde with SnCl2/HCl:
http://www.orgsyn.org/orgsyn/orgsyn/prepContent.asp?prep=cv3...

- then standard reaction with nitroethane and hydrogenation.

Alternatively, 2-naphthaldehyde can also be synthesized by oxidation of 2-methylnaphthalene with selenium dioxide. The synthesis is described in Organikum.

It would also be possible to start from 2-naphthylamine (how is this made? Nitration of naphthalene produces the 1-isomer afaik) and make the nitrile via Sandmeyer.

All this would be completely legal.

haribo - 3-12-2006 at 02:11

64Bandil made and tasted p-F amphetamine. He found it a slightly weaker stimulant than plain amphetamine and slightly 'warmer' so not MDMA-like, but bending in that direction a little. I've tasted DON and it was unlike DOB or DOC. Still very long-lived but MUCH warmer. Much more like a long-lasting 2CB that a full trip (at 4mg at least). I've often wondered why we've got to things like 4 fluoro thioethyl (2CT21) before trying the nitro fully. Animal tests can only show so much.
I remember a stimulant that replaced the benzene ring with a cyclopentyl ring. A five member structure would be very interesting from the POV of adding, say, a methylenedioxy ring.

turd - 3-12-2006 at 03:12

Quote:
BTW would nicodem be so kind to translate that thread from hyperlab?

http://babelfish.altavista.com/

jon - 5-12-2006 at 14:42

I know this deviates from the spirit of (novel aromatic) substituted isopropylamines, but nicodem had posted some reasearch about 4-nitromethylamphetamine made by nitrating plain 'ol meth and it induced a hallucinogenic type reaction in rats at low doses. it's toxicity is high but a little lower than methamphetamine (ld50 68 mg) meth is 55 mg. but the ld 50 of mda is 98 mg so its not outright poison I'll bet that has some potent monamine releasing propertes, nitro fuctions are more electronegative than most on an aromatic ring and that increases receptor affinity.
for something so easily made a human trial would sound interesting enough, those para-substituted analogs have some powerful serotonin agonist action if you consider 4-methylthioamphetamine causes serotonin syndrome.

us patent 5470997 has an example I can't find nicodem's research on the pharmacology of it.
the example is of a sulfuric acid catalysed reaction using a 2-1 h2so4/hno3 ratio. stir in the cold for one hour followed by quenching and, acid base work-up to get 60%.

[Edited on 6-12-2006 by jon]

[Edited on 6-12-2006 by jon]

Nicodem - 7-12-2006 at 10:53

Quote:
Originally posted by garage chemist
I propose a theoretical synthesis of 2-naphthylisopropylamine:

- sulfonation of naphthalene with conc. H2SO4 at 160- 170°C (at lower temperatures the 1-sulfonic acid is preferred, at higher temps the 2-sulfonic acid) to naphthalene 2-sulfonic acid

-fusion of potassium 2-naphthalenesulphonate with potassium cyanide to make 2-naphthonitrile (I do not know if this works)

I don't think you would get 2-naphthalenenitrile by fusing potassium 2-naphthylsulfonate with potassium cyanide. The formation of phenols by the fusion of sulfonates with hydroxides is based on intramolecular oxidation and sulfite elimination, but the cyanide anion is a relatively strong reducent and thermodynamically the potassium cyanate and potassium 2-naphthylsulfinate would be the preferred products. I'm mostly guessing though, as I have not checked the literature. (An analogous reaction however works with the sodium salts of the amines)

Friedel-Crafts acylation of naphthalene generally gives a mixture of both isomers but at certain conditions it can yield the thermodynamic product (substitution at the position 2) as the major product. Here are the two references for the preparation of naphth-2-yl ethyl ketone and a selected one for the naphth-2-yl methyl ketone:

From the naphth-2-yl ethyl ketone (2-propionylnaphthalene) there are so many routes to 1-(naphtha-2-yl)isopropylamine that they are not worth listing. For those suckers worshiping iodine and red phosphorous the following reference might be interesting:
J. Am. Chem. Soc., 57 (1935) 1091-1093.

Here is the reference for Rothman's first paper in connection to 1-(naphtha-2-yl)isopropylamine:
Rothman et al. Development of a rationally designed, low abuse potential, biogenic amine releaser that suppresses cocaine self-administration. Journal of Pharmacology and Experimental Therapeutics, 313 (2005), 1361-1369.

It turned out that this compound was moderately researched after all. Here are the other references:


PS: I know this is completely off the topic of this thread, but then half of the replies in this thread are off topic.

Edit: Added links to patents and corrected a couple of typos.

[Edited on 8-12-2006 by Nicodem]

JohnWW - 7-12-2006 at 11:29

Can someone with the requisite access find those articles mentioned above, and post them here, please? Thanks.

Nicodem - 9-12-2006 at 02:27

Rothman's JPET papers are freely available, but here are also included most others mentioned:

http://www.4shared.com/dir/1469611/b922a46e/1-_naphth-2-yl_i...


As for the thienylisopropylamines, all the papers are here:

http://www.4shared.com/dir/1469744/b5fdce93/1-_heteroaryl_is...

turd - 11-12-2006 at 07:50

Ok, then let me stray even more OT. What about this synthesis route:

Tetralin + HCl + HCHO ----> 3,4-tetramethylenebenzylchloride
3,4-tetramethylenebenzylchloride --(1. Mg, 2. MeCN, 3. NaBH4)--> (3,4-tetramethylenephenyl)-isopropylamine

Two steps, common chemicals.

Nicodem - 11-12-2006 at 15:10

Unfortunately the resulting 3,4-tetramethyleneamphetamine has a highly unfavorable DA/5-HT release ratio of 53. This is surely not as extreme and useless as fenfluramine (a completely selective 5-HT releaser) but it is still quite out of the optimal ratio range. However, some find IAP (1-(indan-5-yl)isopropylamine) interesting even though it has a ratio of 23 (I have no personal experience with it). If taking in account the combined DA and NE release vs. 5-HT release one gets a similar difference between these two compounds, 18 for 3,4-tetramethyleneamphetamine and 7 for IAP. Nevertheless, it might be an interesting compound to some degree, if nothing else for combinations with monoamine releasers too rough on the DA&NE side.

For more information on the compound see:
Nichols et al.
Synthesis and Pharmacological Examination of Benzofuran, Indan, and Tetralin Analogues of 3,4-( Methy1enedioxy)amphetamine.
J. Med. Chem., 36 (1993) 3700-3706.

bio2 - 6-1-2007 at 02:10

Joh posted this comment.

............us patent 5470997 has an example I can't find nicodem's research on the pharmacology of it.
the example is of a sulfuric acid catalysed reaction using a 2-1 h2so4/hno3 ratio. stir in the cold for one hour followed by quenching and, acid base work-up to get 60%...............

This is the example 6 from the patent.

Example 6

Synthesis of p-Nitro-d-Methamphetamine
Hydrochloride

d-Methamphetamine hydrochloride (4.5g, 2.4x10^-2 mol) was dissolved in sulfuric acid (8.5 ml), and the solution was cooled in an ice-water bath. Fuming nitric acid (1.4 ml) was added dropwise to the solution. The reaction mixture was stirred at 0 degrees C for 1h. The solution was poured over ice and 10N sodium hydroxide (35 ml) solution was added to adjust the pH to 12. The aqueous solution was extracted with diethyl ether (3x50 ml). The combined organic layers were washed with deionized water (2x50 ml), and dried over anhydrous magnesium sulfate. The drying agent was removed by filtration and hydrogen chloride (1N) in diethyl ether (25 ml) was added to form the hydrochloride salt. The solvent was removed in vacuo. Acetone (100 ml) was added to the residue and stirred at room temperature for 1 h. The slurry suspension was filtered to give 4.0 g of p-nitromethamphetamine hydrochloride as a white crystalline solid: mp 192-205 deg C.

What would be the result I wonder of doing this using the 70%
concentrated Nitric substituting fuming nitric acid?

Maybe more H2SO4 could be used to bind the extra water?

Most simple aromatic nitrations like benzene or toluene
for example are carried out using concentrated nitric acid at
room or elevated temperature for some hours reaction time.

[Edited on 6-1-2007 by bio2]

Nicodem - 7-1-2007 at 03:02

Quote:
Originally posted by bio2
............us patent 5470997 has an example I can't find nicodem's research on the pharmacology of it.

I have not provided the references for the nitration of (N-methyl)amphetamine except for only one which I considered as exemplary (by McBee et al) simply because they are all more or less the same. Besides the starting material is a controlled substance so it was quite pointless to provide such references.

However I would appreciate if the discussion about p-nitroamphetamine and it N-methyl analogue would be kept in the thread where they originally started as this thread is getting already annoyingly off topic.

bio2 - 7-1-2007 at 16:25

OK, sorry, as I thought this was the appropriate thread.
'
If the moderator would please move this then I won't have
to double post.

My question is simply regarding the suitability of concentrated
in lieu of fuming nitric acid in the procedure I posted from
the patent.

Reference Information

solo - 7-1-2007 at 17:41

Arylethylamine psychotropic recreational drugs: a chemical perspective
Sally Freeman , John F. Alder
Eur. J. Med. Chem. 37 (2002) 527–539



Abstract
The arylethylamines substituted in the aryl ring, side-chain carbons and on the terminal amine, comprise a large number of human mood and behaviour altering chemicals. Some of these psychotropic drugs have been used since pre-history, but in many states are proscribed and are consequently subject to clandestine synthesis and illegal traffic world-wide in the forms particularly of amphetamines and to a lesser extent tryptamines. The chemistry employed in the synthesis of these compounds is dictated often by the available precursors and relies usually on relatively simple, unsophisticated conversion reactions to a suitable product. The internet web sites and documentation of the recreational drug culture have been studied alongside the professional scientific and regulatory literature. The review demonstrates the great complexity of the chemistry and neuro-pharmacology of these chemicals and the challenge faced by legislative bodies to control their traffic and use for the sake of social welfare.

Attachment: Arylethylamine psychotropic recreational drugs- a chemical perspective.pdf (249kB)
This file has been downloaded 1584 times

Nicodem - 8-1-2007 at 13:52

Quote:
Originally posted by bio2
My question is simply regarding the suitability of concentrated in lieu of fuming nitric acid in the procedure I posted from the patent.

There is no reason to believe the concentrated HNO3 (~65%) would not work (if recalculating the volume of HNO3). No extra H2SO4 is required given that it is present in more than 6 molar equivalents. Alternatively you can use ammonium, sodium or potassium nitrates instead of HNO3 and you will have anhydrous conditions (though it is not required). You can even prepare N-methylamphetamine nitrate and slowly add it to sulfuric acid, this way avoiding the exothermic reaction that follows the addition of the free base in the H2SO4 (it is anyway advisable to add the amine sulfate in the H2SO4 instead of the free amine directly). There are a bunch of possible methods for this nitration.
Not that this is very important but the somewhat wide m.p. of the product in that patent procedure indicates there must some ortho-nitro product formed. McBee et al report a sharp m.p. of 186-187°C after recrystallization for the para-nitro product and assume that there is always some ortho product present in the crude products.

Sandmeyer - 10-1-2007 at 16:34

Ok, I seem to be unable find Fast & Bulbou's old stimulant chart (can some body post it?) and I must travel to reach scifinder so I'll ask here. Is anything known about the CNS-effects of diphenyl analog of speed?

Synth of precursor:

http://www.orgsyn.org/orgsyn/prep.asp?prep=cv3p0343 (+ refs therein)

Pardon if this has been discussed bee-4...

PS. Don't have the catalogue at the moment, but 2-methylnaphthalene ought to be cheap. How about radical NBS bromination, cyanide swap/hydrolysis (or make the aldehyde), remaining steps to the final amine are well-documented. Looks like a fun compound. Too bad that G-N hasn't been evaluated as it would be interesting to compare its effects with those of DMMDA...


[Edited on 11-1-2007 by Sandmeyer]

jon - 10-1-2007 at 22:19

I seem to recall reading about someone's expirience with indanyl amphetamine they said it was'nt very enjoyable.

halogen - 16-1-2007 at 06:50

Variant

1723.jpg - 7kB

chemrox - 3-2-2007 at 23:45

Interesting discussion. Is there anything in the 1-(benzofuran-6-yl)isopropylamine related compounds that has been assayed as psychedelic per se? Or the thiophene analogs?

Nicodem - 4-2-2007 at 02:10

I already said this in the first post, but anyway I guess repeating does not hurt too much...
1-(benzofuran-6-yl)isopropylamine and its thio version can not be expected to be psychedelics as they do not fit the SAR for the psychedelics (that is 5-HT2A agonists). They however do fit the SAR of mixed monoamine releasers just perfectly, so they should be expected to be empatogens. The same goes for the regioisomeric 1-(benzofuran-5-yl)isopropylamine and its thio version, though these should have a less favorable DA/NE/5-HT release ratios (according to the same SAR theory). I have yet to see a monoamine release/uptake inhibition study for any of these compounds, though their 2,3-dihydro versions were evaluated by Nichols. But I'll check out if anything else is known on their synthesis, other bioactivity, etc., when time allows.

interesting articles by Nichols et al.

chemrox - 4-2-2007 at 20:33

A.P. Monte, D. Marona-Lewicka, M.M. Lewis, R.B. Mailman, D.B. Wainscott, D.L. Nelson, and D.E. Nichols, "Substituted naphthofurans as hallucinogenic phenethylamine-ergoline hybrid molecules with unexpected muscarinic antagonist activity," J. Med. Chem., 41, 2134-2145 (1998).

or go to http://www.heffter.org/pages/den.html

and find a whole bunch of relevant articles

[Edited on 5-2-2007 by chemrox]

Nicodem - 5-2-2007 at 15:48

The only reference for 1-(benzofuran-6-yl)isopropylamine (I) and 1-(benzofuran-5-yl)isopropylamine (II) I could get is US7045545 (Examples 3 and 1). There are also many others analogues described and lots of interesting chemistry. However, there is nothing on the pharmacology of these two compounds. All the compounds used in formulations and for which we can therefore suppose the title 5-HT2C agonistic activity was effective were of the 1-(benzofuran-7-yl)isopropylamine (III) which means the patent is essentially about the 'halfwinged' so called dragonfly compounds.
Besides this patent I could find no scientific paper about the two compounds. There is something on other potential empatogens like the 1-(benzimidazol-5-yl)isopropylamine, 1-(indol-5-yl)isopropylamine etc., but more about these references some other day.

benzofuranylisopropylamines.gif - 4kB

Drunkguy - 2-3-2007 at 14:22

That Diphenyl analog looks promising. Stuff like that is where the future of chemistry lies.

jon - 2-3-2007 at 15:47

mirapex is a benzothiazole derivitive of amphetamine it's an antiparkinsonian agent that goes directly to d2 receptors. there have been several lawsuits against it, it apparently works too well and causes compulsive behaviors like gambling and sexual promiscuity in otherwise docile individuals.

Nicodem - 3-3-2007 at 00:15

Quote:
Originally posted by jon
mirapex is a benzothiazole derivitive of amphetamine

No, utmost you could call it a cyclic (rotationally restricted) 1-(thiazol-5-yl)isopropylamine derivative if you want to describe it in the context of this thread:

Pramipexole (Mirapex®)

Drunkguy - 3-3-2007 at 01:26

Thats an interesting molecule, certainly ive never seen anything quite like it.

Nicodem - 3-3-2007 at 02:26

Such bicyclic systems where the ethylamine side chain is rotationally restricted by being incorporated in a cyclohexane ring are quite common among the selective agonists at various monoamine receptors. Probably the most known is (R)-8-hydroxy-DPAT, due to its use as a selective 5HT1A agonist.
Note that the stereochemistry of pramipexole is R, thus the opposite of the most active amphetamine enantiomer indicating a completely unrelated mechanism of action (D3 and other DA receptor agonism vs. DA&NE release).

Edit: -------------------------------------------------------------

I mentioned earlier I would provide the references for 1-(benzimidazol-5-yl)isopropylamine. Here are the two references with abstracts that I could find by searching for its structure and that of its tautomere. Anybody able to provide the full papers is welcome to do so.

Evaluation of the NE releasing ability of 1-(benzimidazol-5-yl)propan-2-amine ("decarboxylated I") in heart and brain:
Quote:
Effects of DL-3-(5-benzimidazolyl)-2-methylalanine on brain and heart catechol amines. I. Depleting effects.
Zenker, N.; Morgenroth, V. H., III; Wright, J.; King, J. W.; Arnett, C. D.
Biochemical Pharmacology, 25 (1976) 585-589.

Abstract: DL-3-(5-benzimidazolyl)-2-methylalanine (I) [58894-60-3] (87.6 mg/kg, i.p.) decreased rat brain and heart catechol amines. The releasing potency of decarboxylated I and the inability of I to lower heart norepinephrine [51-41-2] in the presence of a decarboxylase inhibitor showed a decarboxylation product of the amino acid was responsible for the release of norepinephrine by I. When I and then a monoamine oxidase inhibitor were administered to reserpinized rats, the level of brain amines remained const., indicating inhibition of norepinephrine synthesis in vivo; the activity of tissue tyrosine hydroxylase [9036-22-0] in I-treated rats confirmed this inhibition.

Synthesis starting from p-nitroamphetamine:
Quote:
Medicinal agents in the series of beta-phenylisopropylamine derivatives. VI. Benzimidazole analogs of beta-phenylisopropylamine.
Piotrovskii, L. B.; Kudryashova, N. I.; Khromov-Borisov, N. V.
Khimiko-Farmatsevticheskii Zhurnal, 9 (1975) 3-5.

Abstract: Aminopropylbenzimidazole (I, R = H) was obtained in 50% yield in 6 steps from p-O2NC6H4CH2CHMeNH2 by redn., acetylation, nitration, deacetylation, redn., and cyclization by HCO2H. Addnl. obtained was 60% I (R = Me). I have potential sedative activity (no data).


[Edited on 4-3-2007 by Nicodem]

1-(benzimidazol-5-yl)isopropylamine.gif - 2kB

Drunkguy - 4-3-2007 at 09:31

Bravo, excellent material!

Nicodem - 8-3-2007 at 12:23

Well, here we go with another potential empathogen, 1-(indol-6-yl)isopropylamine:
Pharmacology related references with abstracts:
Quote:
Synthetic indole compounds. V. Syntheses of indoles with (2-aminoethyl)-, (2-aminopropyl)-, or alkanolamine side chains on the six-membered ring.
Troxler, Franz; Harnisch, A.; Bormann, G.; Seemann, F.; Szabo, L.
Helvetica Chimica Acta, 51 (1968) 1616-1628.

Abstract: 4-, 5-, 6-, and 7-Cyanoindoles are converted in excellent yields into the corresponding formylindoles by sodium hypophosphite/nickel according to the method of Backeberg and Staskum (1961). Condensation of these formylindoles with nitromethane or nitroethane affords the related nitrovinylindoles, which are reduced to the title aminoalkylindoles by LiAlH4. On the other hand, 5-chloroacetylindole is aminated by reaction with various secondary amines, and the amino ketones formed are reduced to the corresponding 5-(2-amino-1-hydroxyalkyl)indoles. Friedel-Crafts condensation of 1-acetyl-7-hydroxyindoline with ClCH2COCl yields 1-acetyl-4-chloroacetyl-7-hydroxyindoline (I), which is transformed into indoline derivs. carrying a 2-amino-1-hydroxyethyl side-chain in position 4.


Effect of an indole derivative, 6-(2-aminopropylindole), on the general and coronary hemodynamics of the intact dog.
Maxwell, G. M.
Experientia, 20 (1964) 526-527.

Abstract: cf. CA 54, 4912d; 58, 8327a. Measurements were performed on dogs that were injected with the title compd. (total dose of 0.5 mg./kg., 3 injections at 5 min. intervals). The drug has little effect upon respiration. The increase in blood O and the maintenance of satn. are due to the increase in hemoglobin, which is probably due to splenic contraction. The parallel trends in cardiac output and systemic pressure increase both pressure and flow work, but maintain vascular resistance at control levels. The increase of coronary flow is modest and coronary vascular resistance is unchanged. The increase in myocardial O extn. is a function of the increase in arterial O.

Patents on 1-(indol-6-yl)isopropylamine by Hofmann and company:
Quote:
Verfahren zur Herstellung von neuen Indolderivaten.
Hofmann, Albert; Troxler, Franz.
CH442304

Verfahren zur Herstellung von neuen Indol-Derivaten.
Hofmann, Albert; Troxler, Franz.
CH442303

Nouveaux dérivés de l'indole et leur préparation.
Hofmann, Albert; Troxler, Franz.
FR1344579


1-(indol-6-yl)isopropylamine.gif - 2kB

longimanus - 21-8-2007 at 10:49

1-((S)-2-Aminopropyl)-1H-indazol-6-ol: A Potent Peripherally Acting 5-HT2 Receptor Agonist with Ocular Hypotensive Activity
Jesse A. May, Anura P. Dantanarayana, Paul W. Zinke, Marsha A. McLaughlin, and Najam A. Sharif
J. Med. Chem. 2006, 49, 318-328.
PDF

Abstract:
Serotonin 5-HT2 receptor agonists have been identified as a potential new class of agents for the treatment of ocular hypertension and glaucoma. The initially reported tryptamine analogues displayed either poor solution stability, potent central nervous system activity, or both of these undesirable characteristics and were unacceptable for clinical evaluation. A series of 1-(2-aminopropyl)-1H-indazole analogues was synthesized and evaluated for their suitability for consideration as clinical candidates. 1-((S)-2-Aminopropyl)-1H-indazol-6-ol (9) was identified as a peripherally acting potent 5-HT2 receptor agonist (EC50 ) 42.7 nM, Emax ) 89%) with high selectivity for the 5-HT2 receptors relative to other serotonergic receptor subtypes and other families of receptors and has significantly greater solution stability than R-methyl-5-hydroxytryptamine. Additionally, 9 potently lowers intraocular pressure in conscious ocular hypertensive monkeys (-13 mmHg, 33%); this reduction appears to be through a local rather than a centrally mediated effect. Compound 9 appears to be an excellent 5-HT2 receptor agonist for conducting further studies directed toward a clinical proof-of-concept study for this class of ocular hypotensive agents.


Now what is important in the context of this thread are the results of the behavioural tests.
Quote:
Head-twitch induction in rodents, a stereotypical behavior induced by stimulation of central 5-HT2A receptors, has been used to assess the potential side effects of serotonergic compounds. A good correlation has been observed between the rodent head-twitch response for a compound and its ability to invoke a hallucinogenic response in man. However, this response has been shown to be modulated by agonist activity at other receptors, such as 5-HT1A and 5-HT2C, so the results of this assay must be viewed with some caution if other functional data are not available. Selected compounds from the present study along with the well-known centrally active standards 1(R-DOI) and 5-methoxy-R-methyltryptamine (19) were evaluated for their ability to induce a head-twitch response in mice following subcutaneous administration (Table 6). The effective dose required to produce a mean of five head twitches (ED5) during the 10-min scoring period was determined by interpolation of the results from bracketing doses (see Supporting Information); this value was used to provide a relative ranking of tested compounds. The responses observed for 1 and 19 in this assay, ED5 ) 0.13 and 1.0 mg/kg, respectively, were consistent with the reported human hallucinogenic dose for these two compounds, 2.3 and 2-4 mg, respectively. No perceivable response was noted in this assay for 2 (5-hydroxy-R-alpha-methyltryptamine) at doses ranging from 3 to 30 mg/kg, which is consistent with the lack of hallucinogenic activity noted for this compound. As anticipated from the permeability data, 12 ((S)-2-(6-Methoxyindazol-1-yl)-1-methylethylamine fumarate) showed a high level of headtwitch response, comparable to that of 1, with an ED5 of 0.16 mg/kg...

...The 7-methyl (14) and 7-chloro (16) compounds (i.e. 1-((S)-2-Aminopropyl)-7-methyl-1H-indazol-6-ol and 1-((S)-2-Aminopropyl)-7-chloro-1H-indazol-6-ol; yes, that's true - the phenolic compounds!!!) had ED5 values of 0.32 and 0.56 mg/kg, respectively,...
My comments

So, the indazole analogue of 5-MeO-AMT (alpha,O-DMS in TiHKAL) is about 6x more potent than the indole and equipotent to R-DOI. The synthesis procedures suggested in the article are not the type of OTC-kitchen chemistry but still possible. 6-Methoxy-1H-indazole is commercially available and that could make things a little easier (probably the authors started with 6-HO just because they wanted to end with a periferaly acting compounds). For those interested in biochemistry it appears that "the tryptophan synthase alpha 2 beta 2 complex from Escherichia coli has been found to catalyze the beta-replacement reaction of L-serine with indazole" to the indazole analogue of tryptophan (BIZA).

Nicodem - 21-8-2007 at 13:00

Thanks for posting that paper, but at first glance it does not look particularly promising. Some things are however quite interesting in the view of SAR theory. Yet these compounds were already in the patent literature by the same authors (WO0170702) as well as another group (US2004142998).
Isotryptamines (2-(indol-1-yl)ethylamines) and especialy their 2,3-dihydro derivatives are well known to have greater affinity for 5-HT2C over 5-HT2A receptors. Following this SAR direction it is not strange that 1-((S)-2-aminopropyl)-1H-indazol-6-ol and its derivatives also have an affinity for 5-HT2C greater than 5-HT2A receptors. Compounds with this kind of unfavorable 5-HT2C/5-HT2A selectivity are not very promising as psychedelics (quipazine is one such classical compound). Only the compound 14 appears to be a potential psychedelic (Ki = 1.8 nM for 5-HT2A vs. 3.6 nM for 5-HT2C; yet with such a logP it is probably too much peripherally active). I have no idea why this one deviates from the series. Moreover due to the phenolic 6-hydroxy group the penetration of these compounds in the CNS is poorer as it would be in their 6-methoxy counterparts (here the position 6 is equivalent to position 5 in tryptamines).

PS: It seems a pretty straightforward thought that the indazole is an effective bioisostere for indole in tryptamine derived serotonin receptors agonists. Especially as an isostere in tryptamines, but I'm not aware of any 2-(indazol-3-yl)ethylamines having been tested for 5-HT2A receptor affinity. I wish someone could dig out one such study. There are only some old references on the topic:
J. Am. Chem. Soc., 79 (1957) 5242-5245.
J. Am. Chem. Soc., 80 (1958) 965-967.
J. Am. Chem. Soc., 79 (1957); 5245-5247.

longimanus - 21-8-2007 at 23:26

I've worked long enough with animals to know that behavioural tests could not be trusted without serious analysis. However, if these these tests are available then I'd prefer them in front of binding data. And here three compounds were active in the head-twitch.

Comment on receptor selectivity as predictor of hallucinogenic activity:

Yes truely, both DOI and LSD are a little more selective to 2A than 2C - respectively, 0.65:4.0 and 3.5:5.5 (in nM).
And, yes, quipazine is not selective agonist with pKi 2A:2C of 6.4:6.4 (or 6.9) (data from Organon).
However, the so famous S,S-dimethylazetidine analogue of LSD is more selective to 2C - Ki values of 8.3 and 6.5 nM for, respectively, 2A and 2C - and still active at the discrimination study.

I've always had another hypothesis - partial agonism or at least specific modus of activation of the recetor (there is some literature data on the asynchronous firing of serotoninergic neurons in presence of hallucinogenic drugs). Both DOI and LSD are ~ 3x less effective than 5-HT; still (data from article above) the hallucinogenic 5-MeO-AMT is as effective as 5-HT.

I am a little puzzled.

[Edited on 22-8-2007 by longimanus]

A fascinating discussion

dedalus - 22-8-2007 at 03:39

...that I really lack the wit to add to, much, except to say:

The MPTP/induced Parkinsonism fiasco was a great boon to Parkinson's disease researchers, but the unwitting experimental subjects wound up royally messed up.

I'd think about a hundred thousand times before ingesting anything on the basis of rat studies...I hope to contribute to Science, but not by being the victim of the next diabolically selective neurotoxin.

longimanus - 22-8-2007 at 10:00

Quote:
but I'm not aware of any 2-(indazol-3-yl)ethylamines having been tested for 5-HT2A receptor affinity. I wish someone could dig out one such study.
The compounds have been developed - or at least most of the 5-substituted and 1-Me derivatives of the AMT analogue: for example 1-(5-methoxy-2H-indazol-3-yl)propan-2-amine

The fact that the depositors list pharmacologicaly active compounds in their database (not very large one - 24,000 or so) means that these indazoles are evaluated, found active and data has been published. However, I couldn't find anything yet.:(

Nicodem - 22-8-2007 at 12:52

I'm not saying that compounds with 5-HT2A agonism weaker or similar to their 5-HT2C agonism would not be psychedelics. What I was trying to say is that I think such compounds would be "qualitatively inferior". This could just as well be another prejudice since I never experienced quipazine and can't really say what is it that I think would be qualitatively inferior. Also, we can not really say how selective these compounds are in activating the 5-HT2A/2C receptors based only on their affinity since we don't know their efficiency in activating the second messenger production (they might just as well be partial agonists). Furthermore, beyond the receptor selectivity and affinity, the other most important factor is the agonist directed trafficking properties which can differ widely among different structures (not only we know these properties only for a limited number of compounds, we don't even know for sure which one of the second messengers produced by the 5-HT2A receptor complex is actually involved in the psychedelic phenomena).

I would not trust the head-twitch test or any other test based on reflex-like behavior as an indicator of psychedelic activity. That is barely any more certain than the hyperthermic effect in rabbits or whatever other primitive test based on physiological response that was ever used. The only data I would rely upon is a generalization study on rats trained to discriminate LSD, DOB or similar. This is the closer we can currently get in asking a rat: "Are you tripping?" But in absence of such approach I find the affinity data the only truly useful information.

From what I gather in that paper I would still rather opt for the 2-(indazol-3-yl)ethylamines, especially the ones with a 5-methoxy and a small hydrophobic group (Me, halogen, etc.) at position 7 (equivalent to the para position in the PEA psychedelics). The 2-(indazol-1-yl)ethylamines might be an interesting curiosity to pursue, but first things first (just like tryptamines come before isotryptamines...). It is also worthy to consider the possibilities that unsubstituted 1-(indazol-3-yl)isopropylamine and 1-(indazol-1-yl)isopropylamine might also have monoamine releasing abilities in addition to 5-HT2 receptors agonism.

longimanus - 22-8-2007 at 20:51

Quote:
This is the closer we can currently get in asking a rat: "Are you tripping?"
Now this is one of the problems with pain also. We, people in pain physiology and pharmacology research, like to ask ourselves and each other a very difficult question - "How are you sure that the animal experiences pain?". If pain includes emothional component and we cosider animals to be "devoid of emotions" what dives us the right to determine their experience as pain? (Of course rats have emotions - one study showed the existance of empathic feelings, or at least corresponding behaviour; that means one could test for MDMA analogues in rat ;)) But how can you be sure that what the animal experiences on LSD is hallucinations (or at least sensory distortions) and not nausea or warmth (both could be true)? After all psychedelics are ineffective in conditione-place preference.
Quote:
not only we know these properties only for a limited number of compounds, we don't even know for sure which one of the second messengers produced by the 5-HT2A receptor complex is actually involved in the psychedelic phenomena
Also do not forget the facts that:
1. LSD effects are experienced hours after the plasma concentration has dropped below the active range.
2. Even after i.v. application about 1-2 h are needed for fully developed effects of this compound.
If you ask me - there's something with receptor desensitisation and/or protein synthesis.
Quote:
especially the ones with a 5-methoxy and a small hydrophobic group (Me, halogen, etc.) at position 7
I thought that only 7-Me and 7-MeO and not Et or Br were behaviouraly active. Otherwise a very nice idea.

[Edited on 23-8-2007 by longimanus]

Nicodem - 23-8-2007 at 14:02

For me pain includes more of a cognitive component than whatever emotional component. A burn would hurt much less if I would not be able to use language and with it think so much about the pain. Since rats don't have their cognition enhanced by speech, one could argue their sense of pain is different than ours. Kind of like children who only react to mosquito bites after they learn to speak and realize the annoying aspect of the itching. But in drug discrimination tests you don't directly ask the rat to tell you how that drug feels like with the presumption it can experience the drug similarly as humans would. Since rat's cognition is not based on language we can only guess how it feels to them. I would imagine it's something completely different anyway. In reality with these tests it is completely irrelevant how a drug feels like to the animal, because what the rat tells us is how similar a certain test drug is in comparison to the training drug. This therefore does not depend on the actual interspecies communalities of the effects. That's why I think the generalization studies are the most exact animal test possible for testing potential psychedelic drugs. Just think about it. How could a human know a drug has any psychedelic effects unless he experienced the psychedelic phenomena previously? We know what that is only after we have been trained to discriminate it from other types of experiences. Just like those rats are.
Of course, in practice it is much simpler to just try the new compound by yourself, but when one does academic type of research this is not an option.
Quote:
I thought that only 7-Me and 7-MeO and not Et or Br were behaviouraly active. Otherwise a very nice idea.

From the well known pharmacophore of PEA&tryptamines as 5-HT2A agonists it is clear that the equivalence between the two structural classes are:

PEA ortho-methoxy = tryptamine 5-methoxy
PEA meta-methoxy = tryptamine pyrrole ring
PEA para-substituent = tryptamine 7-substituent

For effects of tryptamine substitution at position 7 see:
Studies on Several 7-Substituted N,N-Dimethyltryptamines.
R. A. Glennon, E. Schubert, J. M. Jacyno.
J. Med. Chem. 23 (1980) 1222-1226.

longimanus - 23-8-2007 at 23:09

One dosn't need to understand any language to comprehend pain - there are cases of anencephals who, although without language centers (and almost all other parts missing) are able to feel the pain and express aversive behaviour; this may not br convincing but there's another case - the case of Terri Schiavo - brain damage; "When she emerged from the coma, Schiavo regained a sleep-wake cycle, but did not exhibit repeatable and consistent awareness of herself or environment."; still, "The legal record, however, shows Michael's (husband's) claim that Terri felt pain.". Language is only a tool for the expression of pain, just like vocalisation in rats. And for the understending of pain a developed brain is needed, therefore the learning ofspeaking is accompanied by better comprehension of pain - after all if one tries to feed one's 1-month old baby with hot milk it will deffinately vocalise for the next hours; however this is a stronger noxious stimulus than insect bites.

I agree that discriminative studies have shown good results. But still I'm not sure that what they feel isn't nausea, for example. Laboratory animals have never been exposed to emetics how could they discriminate between regular emetics and hallucinogens with emetic action - training with, for example, emetin or apomorphine are needed. Of course I understand that this is almost cerainly not true, that discrimination studies, especially if combined with evaluation of the behaviour of the animals, is a good test for hallucinogens (whateverthey feel) . Still, there is place for doubts.
Quote:
Studies on Several 7-Substituted N,N-Dimethyltryptamines.
R. A. Glennon, E. Schubert, J. M. Jacyno.
J. Med. Chem. 23 (1980) 1222-1226.
Yes, 7-Br and 7-ethyl substituted 5-MeO-DMT only partially generalised to te parent compound and disrupted behaviour at higher doses.

Nicodem - 24-8-2007 at 11:47

Here is a literature search for compounds of the 2-(indazol-3-yl)ethylamine type, its alpha-methyl derivatives, ring substituted and similar:

The relative potency of 5-hydroxytryptamine-like substances.
Bertaccini, G.; Zamboni, P.
Archives Internationales de Pharmacodynamie et de Therapie, 133 (1961) 138-156.
Abstract: The relative potencies of 78 analogs of tryptamine and 5-hydroxytryptamine (I) were detd. on the smooth muscle of estrus rat uterus, guinea pig ileum, rabbit ear, and the heart of Helix luconum. The most active compds. were I and 5-hydroxy-N-methyltryptamine. The chem. structure changes accompanying decreased pharmacol. activity in rat uterus included: (a) shifting of the phenolic OH group from position 5, (b) substitution on the indole nucleus of groups other than OH, (c) etherification of the phenolic OH with glucuronic or sulfuric acids, (d) lack of any phenolic OH group, (e) shifting of the side chain from the 3 to 2 position. The effect of alkyl substitution on the amino N was variable but usually decreased with increase in size and no. alkyl groups. Substitution of 1 Me group on the alpha C had a variable effect but with 2 Me or 1 Et group substitution there was a decrease of activity. Introduction of an OH group on the beta C of the side chain gave almost total loss of activity. Indolealkylamines with a single C atom lateral side chain had little activity. Indazolealkylamines showed a I-like activity. Results with guinea pig ileum generally paralleled these, while results on Helix heart were less consistent. None of the examd. compds. had marked antagonistic activity. The most active antagonist for rat uterus was N,N'-dipropyltryptamine.

Antidepressant agents. III. Aza analogs of etryptamine.
Carnmalm, Bernt; Misiorny, Alfons; Ross, Svante B.; Stjernstrom, Nils E.
Acta Pharmaceutica Suecica, 11 (1974) 196-200.
Abstract: Etryptamine analogs RCH2CHEtNH2 [R = imidazo[1,2-a]-pyrid-3-yl (I), 1H-indazol-3-yl (II), 1H-pyrrolo[2,3-b] pyrid-3-yl (III)] were prepd. by treating RCHO with PrNO2 and reducing the RCH:CEtNO2. II and III were less active monoamine oxidase inhibitors than etryptamine and I was inactive.

Synthesis and radioprotective activity of  -(3-indazolyl)ethylamine derivatives.
Rao, Erchang; Li, Meijia; Wang, Rongxian; Zhuang, Xianglian.
Yaoxue Xuebao, 22 (1987) 426-432.
(synthesis of 2-(5-MeO-indazol-3-yl)-1-dimethylaminoethane and similar)

US5276051 : Arylethylamine compounds.

US2003171418 : Preparation of pyranoindazoles and their use for the treatment of glaucoma.

WO2002098860 : Novel fused indazoles and indoles with 5-HT2 receptor activity, and their use for lowering of intraocular pressure in the treatment of glaucoma.

WO2001070701 : Preparation of substituted 3-(2-aminopropyl)-5-hydroxyindazoles and related compounds for treating glaucoma.

WO2002098350 : Pyranoindazoles with 5-HT2 receptor activity, and their use for lowering intraocular pressure in the treatment of glaucoma.

WO2000012482 : Preparation of (indazol-3-yl)alkaneamines as 5-HT2 receptor ligands.
(contains affinity and efficiency data for 5-HT2A and 2C receptors for two compounds: 5-chloro- and 5-bromo-indazol-3-ylisopropylamine)

US5385928 : Tetrahydrobenz[c,d]indazoles as serotonin agonists, compositions and use.

[Edited on 25/8/2007 by Nicodem]

Filemon - 2-9-2007 at 03:18

Do you know 1,2,3,4-tetrahydroisoquinoline and derived as 3-methyl-1,2,3,4-tetrahydroisoquinoline? I know little, I only know that they are investigated to treat the narcolepsic (http://www.patentstorm.us/patents/6703392.html). it should be psicoactive because it is a phenylethylamine but anything interesting (I suppose).

[Edited on 2-9-2007 by Filemon]

[Edited on 3-9-2007 by Filemon]

[Edited on 3-9-2007 by Filemon]

longimanus - 2-9-2007 at 22:32

Probably half of the natural alkaloids contain the phenethylamine and tryptamine skeletonin their molecules but most of them are not psychoactive. The abovementioned patent desribes derivatives of 1-benzyl-1,2,3,4-tetrahydroisoquinoline (the skeleton of compounds such as papaverine, narceine, laudanine, etc). The dervatives from that patent are suggested to be orexin antagonists and to be useful in the treatment of obesity (through suppression of apetite) and narcolepsy. However, I am not aware of any of the psychoactive properties Filemon is refering to. Evemn more - orexin antagonists appear to decrease spontaneous physical activity:

Orexin A (hypocretin 1) injected into hypothalamic paraventricular nucleus and spontaneous physical activity in rats
Kohji Kiwaki, Catherine M. Kotz, Chuanfeng Wang, Lorraine Lanningham-Foster, and James A. Levine
Am J Physiol Endocrinol Metab 286: E551-E559, 2004

Abstract:
In humans, nonexercise activity thermogenesis (NEAT) increases with positive energy balance. The mediator of the interaction between positive energy balance and physical activity is unknown. In this study, we address the hypothesis that orexin A acts in the hypothalamic paraventricular nucleus (PVN) to increase nonfeeding-associated physical activity. PVN-cannulated rats were injected with either orexin A or vehicle during the light and dark cycle. Spontaneous physical activity (SPA) was measured using arrays of infrared activity sensors and night vision videotaped recording (VTR). O2 consumption and CO2 production were measured by indirect calorimetry. Feeding behavior was assessed by VTR. Regardless of the time point of injection, orexin A (1 nmol) was associated with dramatic increases in SPA for 2 h after injection (orexin A: 6.27 ± 1.95 x 103 beam break count, n = 24; vehicle: 1.85 ± 1.13 x 103, n = 38). This increase in SPA was accompanied by compatible increase in O2 consumption. Duration of feeding was increased only when orexin A was injected in the early light phase and accounted for only 3.5 ± 2.5% of the increased physical activity. In a dose-response experiment, increases in SPA were correlated with dose of orexin A linearly up to 2 nmol. PVN injections of orexin receptor antagonist SB-334867 were associated with decreases in SPA and attenuated the effects of PVN-injected orexin A. Thus orexin A can act in PVN to increase nonfeeding-associated physical activity, suggesting that this neuropeptide might be a mediator of NEAT.

Full Text (PDF)

[Edited on 3-9-2007 by longimanus]

[Edited on 3-9-2007 by longimanus]

Filemon - 3-9-2007 at 10:11

I have not affirmed that it is stimulating. I have not found information on 3-methyl-1,2,3,4-tetrahydroisoquinoline. But I have found 1,3-Dimethyl-1,2,3,4-tetrahydroisoquinoline it is neurotoxic (it causes parkinson).

Nicodem - 8-9-2007 at 00:14

Quote:
Originally posted by Filemon
it should be psicoactive because it is a phenylethylamine but anything interesting (I suppose).

That is a very stupid and thoughtless claim to say the least!

I have already posted a thorough literature review with references on the psychoactive 1,2,3,4-tetrahydroisoquinolines elsewhere. I'm not sure but you might find the rescued thread from the otherwise dead forum somewhere on the net if you UTFSE. In any case these compounds are completely off topic here in this thread. I think it was already established this thread is about 2-(heteroaryl)ethylamines only.

-TheMadMen- - 29-5-2009 at 08:23

I Am amazed sometimes at the threads and people in this forum. Even the topic of this post "theoretical amphetamine variants" how many of you people are actually professional chemists? Or are you all just amateurs like myself? With an intense passion for chemistry?

As far as amphetamine chemistry goes, isn't it extremely well covered by now? I mean, alexander shulgin for instance, pioneered his findings of phenethylamine chemistry in pihkal, as im sure your all aware. But what's with this bullshit theoretical talk of amphetamine analogs when everybody knows that the two most mind-altering chemical backbones of all in regards to mammals and humans included, are either phenethylamines or tryptamines?? Infact, the most potent, mind-altering chemical of all, if you look at the phenethylamines, is amphetamine itself, the most simple, basic, non-clogged phenethylamine there is, anymore side-chain editions and what not, just dulls the potency, but not necessarily the psychopharmalogical profile.

I Saw something interesting the other day, in some old patent, if you boil dexamphetamine freebase oil in the presence of chloral hydrate, you end up with a molecular change on the amphetamine molecule, which makes it less potent, at least in the mental sense, but still provides superior appetite suppressant abilities. A Good example of how pharmaceutical companies use to, or still do, try and modify basic things, to change there pharmacological profile.


[Edited on 29-5-2009 by -TheMadMen-]

jon - 29-5-2009 at 13:20

the pharmacuetical companies are always on the hunt for ways to push amphetamine under new patents by making salts of amphetamine that have'nt been marketed before which at the end of the day are simply racemic or enatiomerically pure amphetamine salts.

Sedit - 29-5-2009 at 14:24
Quote:
As far as amphetamine chemistry goes, isn't it extremely well covered by now

Not even a little bit. Even as of 1998 substances such as bromo dragon fly made there appearence with a dosage and strength comparable to that of LSD and since then much stronger analogs that target the 5HTP-2a receptors have been synthesized .
Quote:
As far as amphetamine chemistry goes, isn't it extremely well covered by now? I mean, alexander shulgin for instance, pioneered his findings of phenethylamine chemistry in pihkal, as im sure your all aware. But what's with this bullshit theoretical talk of amphetamine analogs when everybody knows that the two most mind-altering chemical backbones of all in regards to mammals and humans included, are either phenethylamines or tryptamines?? Infact, the most potent, mind-altering chemical of all, if you look at the phenethylamines, is amphetamine itself, the most simple, basic, non-clogged phenethylamine there is, anymore side-chain editions and what not, just dulls the potency, but not necessarily the psychopharmalogical profile.


This statement is highly misguided and seems to stem from your narrow areas of research. You seem to forget substances such as PCP and Ketamine, Opiods, Tropine based substances such as Cocaine just to name a small few. Point being where as Phenethylamines and typtamines receptors have the ability to basicly be receptor sluts and accept a whole range of variations this does not conclude that all drugs are based on these skeletons.


@Nicodem
Have you seen any instance in your research that would suggest the use of the structure present in 1-(indol-6-yl)isopropylamine to replace the benzylfuran rings of the Bromo dragonfly variant? Ill generate a structure to give you an idea of what im proposing if needed but this text,

http://www.thevespiary.org/talk/index.php?action=dlattach;to...

States that the singlet hydrogen that is attached to the benzylfuran is what aids in the strong binding to the receptor and the indole variant should at first glance form a simular potancy I would assume.

[Edited on 29-5-2009 by Sedit]

-TheMadMen- - 30-5-2009 at 02:53

Quote:
This statement is highly misguided and seems to stem from your narrow areas of research. You seem to forget substances such as PCP and Ketamine, Opiods, Tropine based substances such as Cocaine just to name a small few. Point being where as Phenethylamines and typtamines receptors have the ability to basicly be receptor sluts and accept a whole range of variations this does not conclude that all drugs are based on these skeletons.


I'm talking more about "mind-altering" as such, while i agree, ketamine in general, and pcp, but more so ketamine, as i find it more fascinating, seems to act more unique than any kind of tryptamine or phenethylamine or even tropane alkaloid, does it not? I Mean, the sensory-isolation that ketamine provides, is well-documented, but what about it's effects on perception? Amphetamine in general, and the slightly less potent methamphetamine, alter perception immensely, but not does as say, lsd, in which your perception of reality is altered, rather, the perception of reality is heightened to such an extent by drugs like amphetamine, that you seem to gain a more rational, wide-scoped, non-forced view of the world, you become like a tiger, or even a tick, a parasite, whereby the only thing on your mind as such, is to use whatever force nessecery to get what you want. Even if it defies "normality", and so i'd consider that to be warping or changing your sense of perception to a certain extent, as by virtue of who we are, humans, have an instinctive mindframe which is to basicallly agree with the "leader of the pack", and in this case, it's society and the law and media, amphetamine reverses that instinct and makes you think for yourself, and possibly those around you with which you love. Like an animal. Which is what makes it so addictive and appealing, or not to mention just the euphoria that it induces, that's what i love about it anyway, heh.

And let's not forget fentanyl, speaking of mind-altering things, and opioids/opiates in general, and as a matter of fact, even imidazopyridine's seem to have some interesting psychopharmacological activity.

And then also ethanol, which is a poison, and so poisons not only your brain, but body too, as do other things, like toxic metals, some mentally insane people on forums like psychonaut seem to think that poisoning yourself with such toxic elements is worthy of a "good trip", i think that they are nutcases, i'm more interested in things that do the same, similiar, or if not better, by emulating the natural neurotransmitters/neurochemicals that our brains handle on a normal basis, so the non-toxic way, as i'm sure you all are too, hehe.

-TheMadMen- - 30-5-2009 at 03:10

It's all very interesting, however, and, baroque, as goes for all psychopharmacology it seems, cocaine for instance, so utterly different to amphetamine in molecular structure, is indifferent in effect profile, while nicotine, with no seemingly profound psychopharmacological effects, seems to incite itself on the conscious mind in it's addictive demands for more of it.

not_important - 30-5-2009 at 04:35

Quote: Originally posted by -TheMadMen-  
...
As far as amphetamine chemistry goes, isn't it extremely well covered by now? I mean, alexander shulgin for instance...


Sedit already addressed this, I will add that Shulgin himself, in a talk he gave at Johns Hopkins a couple of years ago, seemed to feel that there was plenty more to mined from the phenethylamines. Other structure systems are just getting to be rationally understood in their effects, there's much left to be learned I suspect.

Sedit - 30-5-2009 at 06:45

Quote:
Amphetamine in general, and the slightly less potent methamphetamine,


Not to knock your post Madmen because you appear to put some thought into them atlest but where do you get your information from? AMPH is somewhere on the order of 1/10 the potancy of Methyl Amphetamine so once again I am slightly confused by this response.
Quote:
I will add that Shulgin himself, in a talk he gave at Johns Hopkins a couple of years ago, seemed to feel that there was plenty more to mined from the phenethylamines.


N_I speaks the truth and Shulgins is still to this day tinkering with his favorite substrates. One variation I am highly intrigued by is an image that was leaked of Shulgins himselfs lab that showed a blackbord with an image on it that said "make me" under it. It appeared to denote IIRC a substituted carboxylic acid moriaty attached to the alpha carbon and a methylene dioxy one on the benzene ring. This defies most means of normal binding that I know of for other phenylethylamine structures and may point to other receptors of binding hence completly different effects.
Quote:
And then also ethanol, which is a poison, and so poisons not only your brain, but body too, as do other things, like toxic metals, some mentally insane people on forums like psychonaut seem to think that poisoning yourself with such toxic elements is worthy of a "good trip", i think that they are nutcases, i'm more interested in things that do the same, similiar, or if not better, by emulating the natural neurotransmitters/neurochemicals that our brains handle on a normal basis, so the non-toxic way, as i'm sure you all are too, hehe.


This is pretty much what they all do in one way or another including ethanol and PCP. Phencyclidine has its own receptors based all thoughout the body for use in situations of cronic pain and death. This is one of the reasons that some people can be shot or have a limb severed in freak accidents and not feel the pain of it for sometime after.

There are some very good pharmacology websites out there I suggest you look into them you will more then likely find there content truely fasinating.

starman - 30-5-2009 at 18:52

Quote: Originally posted by -TheMadMen-  
Amphetamine in general, and the slightly less potent methamphetamine


@Sedit perhaps he refers the case of substituted phenylisopropylamies where the N-methylated variants are noted as being somewhat less potent as a hallucinogen this of course ignores the very significant qualitative change in the experience caused by N substitution of MDA.

@TMM Its nice to have a new member who has done some reading and bothers to spell properly and I don't want to discourage- but it is difficult to take you seriously on an in depth SAR discussion when you have misunderstood something as basic as this.

Sedit - 30-5-2009 at 20:06

MDA is unusual in its actions also as MDA and MDMA do not appear to form a cross tolerance with each other suggesting different modes of action in ones body. Most methyl amphetamine variants do display a marked decrease from the amphetamine counter parts and this maybe where the confusion is arising from but n-methyl- amphetamine and MDMA appear to show a marked increase deviating from the normal patern that many substituted amphetamines show when methylated.

-TheMadMen- - 30-5-2009 at 22:53

Maybe I should change my name to sunlight. The only reason I called myself "TheMadMen" was because I'd be thought of that way by everybody on a forum like this. But thank you, starman, for your nice greeting. Considering that you live in Western Australia, I am even more impressed, as do I. :-) So hopefully the name "TheMadMen" would not apply after all. :-)

Okay, in my first address, I stated that amphetamine is more potent than methamphetamine, and I stand by this statement for many reasons. How many of you have actually tried amphetamine, d-amphetamine, the dextro isomer, in so far as opposed to d-methamphetamine, or the "ice" and "speed" we all know of?

The truth be known, there isn't actually any noticeable difference in potency in either compounds, most people cannot tell the difference, they are equally fine in there effect, but amphetamine is more potent and lasts longer. The reason it does not turn up all over the place is because its more difficult to synthesize(not really, it's still piss easy, but most people, unbenounced to me, prefer to go through a whole hassle of unnecessary intermediates and steps to get a pathetically unworthy methyl group attached to the molecule). And of course, in the past 10-15 years, when the "pseudoephedrine kitchen bench top cooks" turned up, the only choice they had was to synthesize methamphetamine, as they couldn't just lead to amphetamine directly with one of there ""teqs"" starting from ephedrine or pseudoephedrine alone.

And a methyl group, in other compound families, often downgrades the potency, as is the case with codeine for instance, methyl-morphine. Makes it 1/3 or 1/10th less potent, I forget?

Either way, you get what I'm saying, I hope. And usually a methyl group does nothing to alter the function of the compound's primary function, as would be the case with methylenedioxy ring on the amphetamine molecule, usually all a methyl group does is downgrade the potency, as I have described above, and I'd speculate that the main reason for this is because of bodily metabolism more than anything. The methyl group seems to be a target of many 'an enzymes contained within our bodies.

Sauron - 30-5-2009 at 23:50

This is a chemistry forum and not a lounge for wannabe srug cooks.

If drugs are what you want to talk about, please moey on ober to WetDreams or some similar haunt.

setback - 31-5-2009 at 04:55

I think drug discussion that isn't blatant cookery, "swimming", or other idiocy is fine. I believe that is the policy on this site as well. Besides, have you read the organic forum lately? Sure, there is non drug chemistry discussed, but there is far worse than this.

[Edited on 31-5-2009 by setback]

DJF90 - 31-5-2009 at 05:06

setback: Swim'ing is not allowed on this site. Common sense usually dictates what a posters motive is; whether they have the intention of "cooking" or not. Then appropriate action is taken. Spend a little time in detritus and see what I mean.

starman - 31-5-2009 at 05:44

Well I would have thought any discussion on structure activity relationships of any compound would be acceptable to forum members.Lets not go overboard with political correctness.The reason why compounds behave as they do....Isn't that at the very heart of chemistry?
Lets not not assume the worst of anybody who raises a question in the pharmacological arena.

-TheMadMen- - 31-5-2009 at 05:55

Sauron, read my first post, drugs are not what i want to talk about, and i said i was amazed that people on this forum do want to talk about drugs. So i thought, why not, and went on in and starting engaging in conversation with seemingly like-minded people about these kinds of topics.
Quote:
MDA is unusual in its actions also as MDA and MDMA do not appear to form a cross tolerance with each other suggesting different modes of action in ones body. Most methyl amphetamine variants do display a marked decrease from the amphetamine counter parts and this maybe where the confusion is arising from but n-methyl- amphetamine and MDMA appear to show a marked increase deviating from the normal patern that many substituted amphetamines show when methylated.


Hmm, thought provoking, perhaps, i admit that I've never researched into the interlated-dyanmics of methylated and umethylated amphetamine analogs, or the cross-tolerance that they do not induce, nevertheless, i still fail to see how a methyl group could alter the primary pharmacological action in any way other than to dim it down, as is the case with codeine, as i have described above. Methyl groups do not seem to bind to receptor sites differently, they just actively dim the effect profile down, because maybe more of the drug is removed and metabolized by the body before it can reach the brain etc....

In any case however, from a sociological perspective, let me tell you, methamphetamine is THE amphetamine, that everybody knows about, the most infamous one, but it's also the less potent than amphetamine, that's all i can say, and at the end of the day it is true, believe me or not, or not even less potent, but just as potent, it certainly seems to last longer however, double-blind placebo tests have documented that hardly anyone can tell the difference between a dose of 10mg d-amphetamine and 10mg d-methamphetamine, so explain that?

[Edited on 31-5-2009 by -TheMadMen-]

turd - 31-5-2009 at 06:48

Quote: Originally posted by -TheMadMen-  
How many of you have actually tried amphetamine, d-amphetamine, the dextro isomer, in so far as opposed to d-methamphetamine, or the "ice" and "speed" we all know of?

Not the pure enantiomers, but I tried the racemates of both. Granted, in a completely uncontrolled setting and at a way higher dosage than 10 mg, but I found the opposite to be the case: the N-methyl analogue is gentler but lasts distinctly longer (as in no sleep, not as in euphoria). In the opinion of a colleague "you can't mistake one for the other", but it's not unlikely that this is placebo effect.

PS: over here plain racemic amphetamine is the most common form found on the street.

-TheMadMen- - 31-5-2009 at 07:59

Quote:
but it's not unlikely that this is placebo effect.


Exactly mate. Placebo is the word of utmost importance here. Even a compound as potent as amphetamine/methamphetamine can be swayed to a certain extent by placebo, more people who take meth do indeed seem to expect it to be more "smooth" than normal amphetamine, so as a result it may feel that way, for no other reason than ones placebo cognitive inhibitions however.

But bear in mind, I've never actually tried racemic amphetamine, racemic methamphetamine i have, which may explain why i have always found pure d-amphetamine to be more potent. Who knows. I'm amazed that plain racemic amphetamine is the most common form of crank found on the street where you live. Thats a good thing though, it's about time that people learned the truth, even junkies. :D Here it is definitely meth, but that is soon about to change it seems.

Sedit - 31-5-2009 at 08:54

Without going to far off topic in a threed about THEORETICAL amphetamines I have found some papers that seem to support your hypothesis and where as I in no way shape or form agree with them I do not argue with data. It seems that in females the strength is alot more potant for both forms and that males appear to have a quick peak in potancy but AMPH last and extended period of time.

Without going to far into my past history of drug use I can say that I was perscribed to dl-amphetamine sulfate for years and I personaly feel that the methylated derivative is more potant and way smother then the material that I was perscribed to which lead to shakes and jitters as though one has drank to much coffee. There is a also a noticable fog that ones head is in that is not there for the methyl form. This could be due to what the one text states about METH in that it does not raise GLU levels where as AMPH has a large spike in it.

Mind you these text are based on locomotive basis and not the strenght the material binds to the receptors

Differences between d -methamphetamine and d -amphetamine in rats: working memory, tolerance, and extinction

Quote:

Abstract
Rationale Previously, we have shown that d-amphetamine (AMPH) was more potent than d-methamphetamine (METH) at increasing extracellular levels of dopamine (DA) in the prefrontal cortex (PFC) at doses that had similar effects in the nucleus accumbens. Since working memory depends on PFC DA, it was postulated that AMPH would also be more potent than METH at affecting working memory.
Objective To determine if AMPH is more potent than METH at affecting working memory.
Methods Working memory was measured in adult female Sprague-Dawley rats using a delayed-alternation T-maze task with multiple delays (1, 10, 60 s) and food rewards. The percentage of food rewards consumed was also recorded. Animals were tested with METH and AMPH before and after a chronic protocol, with measurements of locomotor activity used to test for pharmacological tolerance or sensitization. The effects of METH and AMPH on extinction were also examined by omitting the food rewards from the T-maze.
Results Both METH and AMPH produced dose-related bimodal effects on working memory at the intermediate delay (10 s); however, AMPH was more potent than METH. Both METH and AMPH initially also decreased the percentage of food rewards consumed in the T-maze. After chronic testing, animals displayed tolerance to both the working memory impairments and the reduction in food reward intake produced by AMPH. Animals did not display significant tolerance to the effects of METH on food reward consumption and performed worse in the T-maze after chronic testing. METH, but not AMPH, interfered with extinction.
Conclusions These results indicate that METH and AMPH differ in altering working memory and the expression of tolerance, perhaps due to differences in behavioral inhibition.


Reference:http://www.springerlink.com/content/jdppjuv480ueb7xv/

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=18...





As stated before this is a threed for theoretical amphetamine variants and mounds of information can be found thru a quick web search.

But I will attach a picture of a substance I have intrest in because a complete search of PubMed has turned up not a single bioassay of the substance. As you can see it is nothing more then an indole variant of the bromo-dragonfly compound and it includes all the prerequisites for receptor binding such as two singlet hydrogen doners and a reqion of steric occlusion just like the Bromo-dragonfly molecule.



bromoflyindole.JPG - 4kB

-TheMadMen- - 31-5-2009 at 09:16

Thanks for posting that article Sedit, it definitely seems to agree with my statement that amphetamine is more potent than it's methylated analogue. But like you said, even yourself would say that on a subjective basis, you found methylated amphetamine to be more appealing on many levels.

If I read it correctly, amphetamine induces more dopamine release than methamphetamine? In rats. Surely that would be the calling card for such a claim as I would make as to the superior strength of amphetamine to methamphetamine on a physiological basis? But again, subjectively, that may not be the case!

In regards to the bromo-dragonfly, I admit I never really heard of it, but if it has a potency similar to LSD, then I am instantly fascinated by it, I've never really heard of a compound having such a potency, or infact, clonidine, I think, not a psychedelic substance, but I think it is still dosed on the microgram level. Seems to be a drug that comes to mind in that regard. Oh, and fentantly, and the super potent opiate analogs. But what the hell, i am veering off course here immensely, forgive me, we are talking about theoretical amphetamine variants hehe, not clonidine or opiate analogs. But anyway, yeah, I'm stunned at the bromo dragonfly. I Admit. Seems interesting.

[Edited on 31-5-2009 by -TheMadMen-]

[Edited on 31-5-2009 by -TheMadMen-]

Arrhenius - 31-5-2009 at 09:30

Sedit: I see no reason why the structure you've drawn would be a good candidate. Nitrogen is not an isosteric replacement for oxygen here. Personally, I wouldn't take that. Aromatic amines are generally not so good for you. I'd like to discuss more the SAR aspects, which no one has really brought up.... what about bromo-dragonfly lends well to increased potency. Bulk? Non-polar interaction? Secondary pharmacophore (if so, what is it?)

How much work, beyond old-school SAR, has been done with the 5-HT2A receptor?

Sedit - 31-5-2009 at 09:46

Arrhenius I would not take it either because Bromofly compounds have a bad habit of causing vascular constriction sometime days or weeks later leading to gang green and loss of extremities. That being said read the paper I posted on the page before this one and it will explain why I feel this would be a good candidate for receptor binding. The oxygens on the furan rings donate a hydrogen to the receptor and lead to a strong interaction with the binding site.

Arrhenius - 31-5-2009 at 11:40

I've never heard that. In fact I find it hard to believe (not saying I don't trust you, I just don't trust lots of stuff on the net). On that note, however, aren't all amphetamines and relatives a bit hypertensive? I guess I don't see a good reason why a drug can have real adverse effects a week later.

Yes, I realize that the Br-dragonfly probably benefits from H-bonding at the furan, but in my experience :NH is a much poorer H-bond donor. I would not be surprised if its pyrrazole analog is not very potent.

It has somewhat been brought up earlier, but how active would the purely steric analog be? This is comparable to the indane structures which have been discussed. I would not be surprised if this is more active than amphetamine purely due to hydrophobic interaction. I'm not under the impression that the choice of 4-halide should matter, since it's blocking hydroxylation and realistically has minimal ADME impact. This will probably suffer from high protein binding, but give clues as to the value of furan:
steric_analogue.gif - 2kB

Sedit - 31-5-2009 at 12:22

From Wiki of all places,
Quote:
Toxicity

Pink ABDF powder.The toxicity of Bromo-DragonFLY is unknown for humans however at least three reports of death believed to be resulted from Bromo-DragonFLY have been reported in Norway[3], Sweden[4] and Denmark[5][6]

Also, a Swedish man had to have the front part of his feet and several fingers on one hand amputated after taking a massive overdose. Apparently the compound acted as a long-acting efficacious vasoconstrictor, leading to necrosis and gangrene which was delayed by several weeks after the overdose occurred. Several other cases have also been reported of severe peripheral vasoconstriction following overdose with Bromo-DragonFLY, and a similar case is also known from DOB. Treatment was of limited efficacy in this case although tolazoline is reportedly an effective treatment where available.[7][8]

Overdoses, disturbing experiences, and Bromo-DragonFLY associated health problems have been described. One case in 2008 in England involved inhalation of vomit, causing nearly fatal asphyxia.[9]


I have many more papers that I will look for later tonight. The problem is the vascular constriction does not go away quickly and after an extended period of time for lack of blood flow to the extremities causes gangrene to set in and causes necrosis of the tissue.

I have not seen any synthesis of the compound you mentioned but I will keep an eye out as I look around later.

Arrhenius - 31-5-2009 at 13:46

I haven't either, and it surely wouldn't be easy. The published syntheses for dragonfly & hemidragonfly analogues are not exactly simple either.

I saw that on wikipedia, but my issue is that I'm not sure I trust Erowid. The resources available to Erowid are limited, and the forensic evidence is too. I find the gangrene case to be extremely peculiar and not representative.

Also, all 'reported' (near)fatal hypertension seems to be as a result of overdose. Is this a good way to measure safety? I should think safety would be better gauged by the number of safely consumed *reasonable* dosages.

ScienceSquirrel - 1-6-2009 at 05:00

It is quite probable that a lot of these compounds may have been prepared but never made it into the published literature.
Quite a lot of chemistry never gets published as there is nothing particularly original about it or the compounds have no interesting properties.

Arrhenius - 1-6-2009 at 08:33

Haha. People publish uninteresting stuff all the time!! :P But very little gets published relating to psychopharmacology now anyway. Some of the questions posed above would be considerations for a modern chemist doing 3D QSAR, but probably not for Dr. Shulgin & co. who did purely homologation (somewhat randomly).

ScienceSquirrel - 1-6-2009 at 09:17

Good point, there are lots of useless and boring publications out there.
I have had to look up compounds where I was sure that there would be lots of homologues, only to find obvious and easy substitutions not listed in the literature.
I am sure they have been made but never made it out of the world of theses and internal reports etc.

Sedit - 1-6-2009 at 09:48

I retract what I said before about nitrogen being a substitute for oxygen because I misunderstood what I read before and the hydrogen bond doner is comming from the receptor and not the substance itself not only that but the whole charge of the area would be all wrong and quite possibly just repel the receptor site. With that being said what about a sulfur analog? The area of influence for accepting the hydrogen bond would be greatly increased and as long as the size is not to large possible create a stronger binding the oxygen.


For those of you who haven't taken the time to read the paper I uploaded(shame on you) I will attach the receptor conditions here, Also is a picture of the difference in area of interaction that sulfur would cause

sulfur.gif - 13kB

bromoflybond.JPG - 14kB

Arrhenius - 1-6-2009 at 18:30

Eh... I don't want to sound like a downer, but that's an utterly oversimplified model. "H-bond donor" is rather ambiguous. Did you draw that? One would love to think it binds like that, but why should that be a multitude more potent than 2C-B?

Sedit: Do keep in mind that a :NH lone pair can act as a hydrogen bond acceptor, but not really when conjugated in a ring, e.g. Sulfur is an isosteric replacement for oxygen, but it doesn't usually make much sense, as it's oxidized to the sulfone pretty readily by CYPs. The only paper I see is the one you linked on female v. male rats. That one?

Seeing as how the duration of bromo dragonfly & friends seems to be rather long, I would be interested to see the duration of the 4-H phenyl analogue. This is an intermediate, but I can't find any bioassay.

Sedit - 1-6-2009 at 21:30

No the paper is page or so back that I got that picture of the binding mechanics from. Its not attached, its in a link in one of my post. Im sure it is a highly over simplifyed model and the text goes into more details but that is the jist of why this binds so strong to the receptors.

IIRC the reason its so much more potant the 2C-B is because the closed ring structure prevents rotation of the oxygen bonds fixing it into a stable position. This has been used in other variants of amphetamines also to attach a cyclopropane to the "tail" to stiffen it and enhance potancy greatly. Over at blacklight you will find information about that substance and alot more then I could possibly ever know about this one also.

Arrhenius - 2-6-2009 at 09:29

Yes, I'm familiar with the cyclopropyl derivatives (which are probably legal). I'm not really a forum surfer; you won't find me elsewhere. I don't care to read forums strictly about drugs, since it's the chemistry I'm interested in. I would propose that a larger molecule might be higher potency simply because of hydrophobic interaction in the receptor binding pocket. Researchers often overlook the enthalpy gained by displacing a few water molecules (also incredibly difficult to calculate). Hence, I would love to see the steric analog i brought up. I think for this reason some of the pyrrole derivatives mentioned earlier will not work.

Personally, I'd like to see more experimentation on the aliphatic end of these molecules. Clearly phenethylamines and tryptamines can accept a wide variety of N-alkylation. A derivative of LSD exists in which all but the indole ring are opened to give a long chain. I can only presume LSD-25 is a highly privileged structure, given its potency. There is a very good chance that the molecule hits a secondary pharmacophore of the 5-HT receptors. What do you think? Start here, or the indole.

analog.png - 31kB

Ah... I'm sorry for straying off topic, this isn't an amphetamine.

[Edited on 2-6-2009 by Arrhenius]

Nicodem - 2-6-2009 at 22:34

That topic was already discussed some time ago: http://www.sciencemadness.org/talk/viewthread.php?tid=8120

Arrhenius - 3-6-2009 at 08:19

That's a different molecule, but thanks, I hand't seen that thread.
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