Sciencemadness Discussion Board - SILDENAFIL CITRATE

SILDENAFIL CITRATE

syed - 11-1-2007 at 21:39

hey guys i doing a project on Sildenafil Citrate and i finally found out all the functional groups but i have no clue what the functional groups do to make viagra viagra. I know theres a ether group, amine, amide, sulfonyl group, sulfonamide, a benzene ring, and finally an alkene but i dont know what these do.

[Edited on 12-1-2007 by syed]

bereal511 - 11-1-2007 at 22:17

All parts of the sildenafil molecule takes on a shape designed to selectively bind to the enzyme cGMP specific phosphodiesterase, which catalyzes the destruction of the guanosine monophosphate in the body. With cGMP specific phosphodiesterase disabled in the body, guanosine monophosphate is free to act on the muscle cells in the penis, which causes muscle relaxation. This in turn allows blood to flow more freely, giving erections. Now, if you wanted how each individual functional group attaches to the enzyme mentioned beforehand, you should probably research more in depth on the binding mechanisms of sildenafil and the corresponding chemical structure of phosphodiesterase. There's not much that the functional groups do on their own to lock onto the enzyme, its the structure of sildenafil as a whole, though the nitrogenous and oxygenated functional groups play the strongest role in their Van der Waals attractions to the enzyme.

Sauron - 12-1-2007 at 00:38

Be aware that sildenafil only works (promoting vasodilation) on males who suffer from specific typed of erectile dysfunction. And then it only works if the subjects have external erotic stimulation.

In short if you don't need it, it does nothing, and if you aren't being stimulated it still does nothing. It is not an aphrodisiac.

The synthesis of sildenafil is rather long and complex.

There is now a true human aphrodisiac, one that directly stimulates the libido and it is effective on both men and women, It is not a vasodilator. It is a synthetic cyclo heptapeptide analog of alpha-melanocyte stimulating hormone. and it is called Bremelanotide or PT-141,

It has the structure:

Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-OH

All those seven amino acids are L-isomers except for the D-Phe.

This stuff is in FDA Phase III trials already as treatment for female sexual dysfunction. It belongs to Palatine Technologies of New Jersey.

Sauron - 12-1-2007 at 00:55

And the three rings in sildenafil are a pyrazine, a substituted phenol and a piperazine.

One of my Irish friends is the process engineer at Pfizer in Dublin where they used to make the stuff. Now they have licensed it out and are busy making Lipitor there.

The original, and the improved Pfizer processes for sildenafil were posted on Rhodium and are in the literature. There are no trade secrets involved. It is widely knocked off in bulk in India, China and North Korea, also Cambodia. Bulk sildenafil citrate sells for about $2000 a Kg. Having studied the prep in detail I would not make it for that price. Too damned much work.

[Edited on 12-1-2007 by Sauron]

Polverone - 12-1-2007 at 01:18

Quote:

Originally posted by Sauron
Be aware that sildenafil only works (promoting vasodilation) on males who suffer from specific typed of erectile dysfunction. And then it only works if the subjects have external erotic stimulation.

In short if you don't need it, it does nothing, and if you aren't being stimulated it still does nothing. It is not an aphrodisiac.

The synthesis of sildenafil is rather long and complex.

There is now a true human aphrodisiac, one that directly stimulates the libido and it is effective on both men and women, It is not a vasodilator. It is a synthetic cyclo heptapeptide analog of alpha-melanocyte stimulating hormone. and it is called Bremelanotide or PT-141,

It has the structure:

Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-OH

All those seven amino acids are L-isomers except for the D-Phe.

This stuff is in FDA Phase III trials already as treatment for female sexual dysfunction. It belongs to Palatine Technologies of New Jersey.

Now there's a license to print money. How is it synthesized? I know little about peptide chemsitry, but I do know what sort of spam will be clogging my inbox in a few years.

Sauron - 12-1-2007 at 02:35

You don't need a crystal ball to see that one coming, for sure. The Indians and the Chinese (The Usual Suspects in this racket) are already on it.

Peptide synthesis is not a cakewalk. At the minimum the stereochemical issues are daunting, HPLC requires a pretty serious investment on a preperative scale, the protecting group selection and coupling strategy decisionmaking is tricky, and in the case of this relatively simple heptapeptide, the cyclizing step is low yield.

Life's a bitch.

I am leaning toward Fmoc strategy rather than Boc.

I have about $40,000 invested in second hand Waters analytical and prep HPLC systems at this point. And that is on a scale to clean up grams per injection.

This is my major project, it is quite challenging and I will be at it for years (already about 1.5 years). I have zero ambition to sell it, I just want to see if I am good enough to make it and purify it. It does have the advantage over some other challenging molecules of not being illegal and of not requiring any suspicious reagents (unless D-Phenylalanine is.)

One of the amino acids, Nle (L-Norleucine) is not very available commercially. It is easy to make in racemic form and the problem then is to resolve it. Best done enzymatically with papain Nle is an unnatural amino acid used as an internal standard in instrumental analysis of amino acids, To build it, you alpha-brominate caproic acid, treat that with conc ammonium hydroxide and you have DL-Nle. That much is dead simple. It's all in Org.Syn. The enzymatic resolution is in J.Biol.Chem. and can be had for free online.

All the other amino acids are off the shelf.

I am digitizing two great books on peptide synthesis by M.Bodanszky, one is a text and the other a lab manual. Eventually I will upload these to MadHatter.

Sauron - 12-1-2007 at 02:53

The hormone a-MSH from which Bremalonotide is derived is produced in the human posterior pituitary and as the name "melanocyte stimulation hormone" implies it regulates skin pigmentation (melanin). Most reptiles, amphibians, fish and all mammals have MSH, a 13-amino acid peptide. The first six residues are species specific. The last seven are the business end and are always the same. Bremelanotide is a modification of that part of a-MSH. The Univ. of Arizona was after an oral sunless tanning agent (take a pil, get a sun tan) so that people who wanted a tan would not have to sunbathe or sit under UV lamps and be at risk of skin cancer. They came up with two products, Melanotan and Melanotan-II. The latter had an unexpected side effect. It made test subjects horny. Further tsting demonstrated that it induced erections even in older males with erectile dysfunction (ED) and that it also produced an erotic response in women. This effect occurs in complete absence of external stimulation unlike Viagra etc, and this substance, now given the generic name Bremelanotide, is regarded as the first of an entirely new class of pharmaceutical agents and is on a fast track to FDA approval. The development of the sunless tanning agent has been seperated from that of the aphrodisiac; Bermelanotide does not give you a tan and Melanotan-II no longer makes you horny. The Bremelanotide side is licensed exclusively to Palatine Technologies who call it PT-141.

The ED is 20 mg. Higher doses induce nausea.

Sauron - 12-1-2007 at 03:02

Although peptide chemistry is difficult there are many many commercialized pharmaceuticals that are peptides and the pharm industry mass produces them, purifies them by HPLC, they know what they are doing. Many of these are substantially more complex than Bremelanotide. 10-20 amino acids compared to only 7 in Bremelanotide. Human insulin is over 100 amino acids. It is now produced synthetically.

Reverse phase HPLC can seperate insulins that differ by a single methyl group. One -CH3 in a peptide of 100 amino acids. Incredible. In RP there is a pH gradient and the individual peptides fall off the stationary phase one by one as the pH changes.

Sauron - 12-1-2007 at 03:13

Here's food for thought.

Serendipitous discoveries like the unexpected side effect of Bremelanotide, rarely are fully optimized for the specific effect.

That means there is a lot of SAR yet to be done. (Structure-activity relationships). But what this discovery has done, is to open the door to direct stimulation of primary human emotions.

If we can (accidentally at first) trigger the libido, perhaps we can manipulate gender identiry. Perhaps we can have an effective therapy for paedophilia. Everything is neurochemistry. Here we have tumbled upon an insight into human neurochemistry and we will throw that door open wide, walk the corridors and peer through the other doors. In some ways this is very exciting. In some ways this could be very frightening. I suppose we can all agree that a cure for child molesters that is more humane than chemical or actual castration, or institutionalization, is desirable. But there is much less likelihood of consensus on a "cure" for homosexuality for example. Simply because there won't be a consensus on whether or not it is a pathological condition in the first place, right?

Oh brave new world!

Maya - 12-1-2007 at 04:32

One-Eyed Guy Wrote:

<<<< In RP there is a pH gradient and the individual peptides fall off the stationary phase one by one as the pH changes >>>>

You're starting to take a walk on the wild side here.

In RP there is a Non-polar to Polar gradient NOT a pH gradient. Typically Acetonitrile in water going from 10% to as high as much as 90-100% acetonitrile.

Surprised you would invest so much and not know this.

[Edited on 12-1-2007 by Maya]

Sauron - 12-1-2007 at 04:46

@Maya I am talking about quad RP, with one of the compenents being an aqueous high concentration of (usually ammonium) salt. Of course there is a pH gradient and it is the pH gradient that knocks off the peptides (or amino acids) one by one with such high selectivity from their perches on C4 to C18 stationary phases.

Maya - 12-1-2007 at 05:16

Sounds like you're doing ion exchange chromatography instead.

I've never heard of Quad Reverse-Phase Chromatography, and I've done my share of RP.

In RP it is the increasing non polarity that knocks them off their perches. in ion exchange it is increasing ion concentrations.

You gotta pick one column c14 or c18, or are you saying you have them in tandem?

Sauron - 12-1-2007 at 05:34

For two component systems such as H20/MeCN your description is spot on.

And in fact the extreme examples I was thinking of (seperation of human vs rabbit insulin which differ only by a single methylene) were such systems.

I am hunting around on ht HDD for a description of a 4-component (hence, quad) RP procedure, with a pH gradient, and I will post it if and when I find it. If I can't I will own up to having misspoken. Fair enough?

I'd best know what I'm about with this as I really have dropped all that $$$ into five Waters 600E analytical systems, two PrepLC 4000 systems, a 650E Advanced Protein Purification System, a pile of 486, and 490E UV detectors, a 994 PDA, and Millenium32 workstations to run it all on IEEE-488 buses. Not new but in good shape. Spares are for redundancy and for cannibalizing for parts in instances where Waters no longer supports the model (as with the 490Es).

Sauron - 12-1-2007 at 05:37

No the only thing I use ion exchange chromatorgraphy for is desalting after global deprotection and before HPLC. Done on CMC.

Have you got DryLab?

If so look for RP Gradient/pH as they have examples of this technique.

No I was not talking about two columns in tandem, just giving a useful range of bonded phases.

[Edited on 12-1-2007 by Sauron]

Maya - 12-1-2007 at 06:17

Gotcha , 4 component liquid RP is a better descriptor.

<<< Have you got DryLab? >>>

No, I haven't worked on HPLC in > 10 years. However we are working on a synthetic D-amino acid peptide, 10 AA, that we will be making 20 construct variants of pretty soon so we may invest in a new state of the art system soon.

Thats alota green to drop into satisfying your curiosity when there doesn't appear to be exclusivity or maybe even optimization yet.

side note , maybe we should also look into some SAR modeling sofware as well but I haven't much practical knowledge of these systems for our peptide receptor work.

Sauron - 12-1-2007 at 06:33

Are you using Merrifield (automated synthesizer) techniques, i.e., solid phase, or classical wet lab preps?

I can't afford the former so I am planning the latter.

Also I like to see some product rather than a smudge at the bottom of a sample vial. Just a personal prejudice.

10 AAs not too bad, is it linear or cyclized?

Yes $40K a pretty penny to see go over the event horizon of the black hole of a money pit that is my hobby. But I don't have any kids, am well off, and thus I indulge myself.

Besides I figure I might have other uses for this stuff down the road. At least that's what I keep telling myself to assuage the pain in my wallet.

[Edited on 12-1-2007 by Sauron]

Maya - 12-1-2007 at 06:53

So far our cost has been ~$2k a gram.
We've outsourced till now but 20 variants would be well over $35K so may be cheaper to do inhouse. if we do, we have a core that says they have a robotized peptide synthesizer, don't know if its merrifield. Otherwise it might take me awhile if I have to do it all myself wet wise.

Linear peptide, I would imagine you end up with smudges more often on cyclization attempts

Maztec - 12-1-2007 at 07:01

the mode of action of slidenafil
http://www.ch.ic.ac.uk/local/projects/p_hazel/mode2.html

synthesis of slidenafil
http://www.ch.ic.ac.uk/local/projects/p_hazel/synthesis2.htm...

Sauron - 12-1-2007 at 07:16

The standard cyclizing agent for the heptapeptide, linking the Asp and Lys side chains, is DPPA (diphenyl phosphoryl azide.) Yields are rather low. 15-20% IIRC.

I have read about superior cyclizing reagents but they remain rather exotic and I have not heard of their use in this application being published.

Even DPPA does not seem commercial, it is prepared from diphenyl phosphoryl chloride and NaN3. The details are in Bodanzsky, The Practice of Peptide Synthesis.

Sauron - 12-1-2007 at 07:25

@Maztec, that's the earlier prep of sildenafil. Pfizer worked out a much better route and two of their chemists published it in one of the major journals.

The order of steps is different.

They replaced the politically incorrect SOCl2 with CDI (carbonyl diimidazole) a peptide coupling reagent.

Other improvements I can't recall.

Both the procedure you posted and the improved Pfizer process were up on Rhodium years ago. Which is where I saw them.

Maya - 12-1-2007 at 07:28

You've got a His and Tryp in close proximity as well , that is unusual.

wonder how much of the low yield is due to stereoisomeric strain and how much is due to non-specific rxns

did you get u2?

Sauron - 12-1-2007 at 07:57

Sorry @Maya no u2 here yet.

I don't know why the low yield.

The His is Bom protected, the Trp is N-formyl. These are knocked off just prior to cyclizing.

Jdurg - 12-1-2007 at 15:02

Guys, don't forget that Sildenafil isn't a compound that only works on the male penis. It works throughout the entire body. The fact that the penis becomes erect is simply a beneficial side effect. If you don't have erectile dysfunction and take Sildenafil you may still experience some of the effects of the drug which may not be too good for you. Sadly, people don't bother paying attention to how a drug works. They just believe what they read in the media and this leads to a lot of tragic results.

I really wish I could go into more detail about Sildenafil and it's other uses, but the NDA I signed when I became employed by Pfizer PGRD prevents me from saying anything further. The only thing I can say is that Sildenafil is being tested on more than just penis problems.

Sauron - 12-1-2007 at 22:50

If I recall the trials during which the "payday" side effect was noted, was for a beta-adrenergic.

Some other side effects are well known: color shift in vision (blue-green shift).

Many of the knockoffs are notorious for headaches, perhaps their QC sucks. Personally I'd stick to the real McCoy. And then only if it is needed.

There is a famous contraindication: do not combine with organic nirites/nitrates. One vasodilator potentiating the other. Can be fatal.

Sandmeyer - 13-1-2007 at 03:42

Quote:

Originally posted by Sauron

There is now a true human aphrodisiac, one that directly stimulates the libido and it is effective on both men and women.

True, it's called GHB...

Organikum - 13-1-2007 at 04:33

Quote:

Originally posted by Sandmeyer

Quote:

Originally posted by Sauron

There is now a true human aphrodisiac, one that directly stimulates the libido and it is effective on both men and women.

True, it's called GHB...

Funny I told him that before but Sauron is a strong believer in tanning agents......

Sauron - 13-1-2007 at 04:44

You are confusing an intoxicant with an aphrodisiac.

PT-141 (Bremelanotide) has no intoxicant effects.

And GHB has no effect on erectile dysfunction, female sexual dysfunction, or the libido.

GHB GHBA etc tweak the GABA system and increase electrical activity in the brain.

If it were not for Hillary and her feminazi friends getting all hyped up about the phony date rape issue, GHB would still be OTC in health food stores.

By their arguments beer ought to be Schedule 1 DEA because I am quite sure a lot more dates have been "raped" under its influence than by GHB and Rohypnol combined. Alcohol is the archetypal date rape drug. By which of course what I mean is the whole thing is a CROCK.

Bremelanotide is another matter entirely.

Similar inaccurate claims were made regarding MDA/MMDA, even methaqualone. These are not aphrodisiacal in any true sense. Bremelanotide is.

Don't confuse the marketing ploys of drug dealers with science.

Or substitute wishful thinking and imprecision for cold facts.

[Edited on 13-1-2007 by Sauron]

Sauron - 13-1-2007 at 04:59

Tell it to the FDA and Palatine Technologies, @Organikum.

The latter will become very very wealthy very soon.

All anyone gets for GHB is hard time in the slams, it's Schedule 1. Rightly or wrongly it's Schedule 1. Alongside heroin and cocaine.

Nicodem - 13-1-2007 at 05:05

Quote:

Originally posted by Sauron
You are confusing an intoxicant with an aphrodisiac.

Nonsense. An aphrodisiac is any compound that increases libido. For me cannabis is an aphrodisiac and the side effect of being 'stoned' does not bother me at all when having sex.

Quote:

PT-141 (Bremelanotide) has no intoxicant effects.

Sounds like an extremely boring drug.

Quote:

And GHB has no effect on erectile dysfunction, female sexual dysfunction, or the libido.

GHB just like alcohol releases the cultural inhibitions and thus makes people horny among other things. Note that sexual dysfunctions are generaly symptoms of neurosis and are only rarely physiological in origin.

Sauron - 13-1-2007 at 05:35

@Nicodem, I agree entirely with your assessment of GHB viz ethanol. Spot on.

I think you vastly understate the occurance of both male and female nonpsychosomatic sexual dysfunction. There is a huge market, Pfizer has amply demonstrated that for male ED. Viagra is not an aphrodisiac, but for people with ED it is a godsend. You are suggesting that since per your statement ED is a neurotic symptom most of the time, it would follow that a placebo diamond shaped blue pill would work just as well. That is not the reality.

And your assertion that cannabis or anything that makes you horny is a true aphrodisiac in the clinical sense, is simply untrue.

I think cannabis functions as a simple intoxicant much like alcohol and as you agreed GHB, lowering inhibitions. Lowering inhibitions does not promote sexual desire in males and females without any external stimulation, and most certainly not in those with sexual dysfunction.

Sildenafil only works to promote erections in men with ED and with external stimulation. No external stimulation no erection. Zero libido enhancement.

Sildenafil also has no erectile enhancing effect on males without ED with or without external stimilation. If you don't require it it will not work. If you don't require it and take a placebo and have external stimulation you will get an erection anyway.

QED Sildenafil is not an aphrodisiac.

Yet Pfizer have gotten fat off the ED market.

Bremelanotide has same market plus female market. Not being an intoxicant, it is not at all like Rohypnol, is nonhypnotic, nonsedative, and does not induce memory loss. It is not at all like GHB.

I do not believe it would be succesful if administered surreptitiously to a woman (or man) not otherwise inclined to have sex with the person giving it. They will get horny and then go seek a partner they desire, if the person sitting next to them is not a candidate. We are not talking about a substance that produces indiscriminate satyrs and nymphomaniacs. Watch out for the wishful thinking again. Enhanced libido is not loss of free will.

I think Bremelanotide has great potential to be socially and politically controversial. The religious right will hate it. The moralizers will condemn it. The feminazis will denounce it and if Hillary gets in it's all over at least in USA. But, that may not come to pass.

I think Palatine will get stinko rich and I think @Polverone got it right. So will the knockoff manufacturers. Indian and Chinese Big Pharm. Spam. Internet sales. No place in there for the likes of little me, for me it's just another personal project.

Sandmeyer - 13-1-2007 at 07:19

The post has been edited due to a irrational pertsonal insult...

/Sandmeyer

[Edited on 13-1-2007 by Sandmeyer]

Sauron - 13-1-2007 at 07:38

Thanks to the Moderator(s) for swift attention.

[Edited on 13-1-2007 by Sauron]

Sandmeyer - 13-1-2007 at 07:53

Sorry for that, I don't know why I posted something as stupid as that, wasn't thinking before posting...

Organikum - 13-1-2007 at 09:46

Quote:

Originally posted by Sauron
Tell it to the FDA and Palatine Technologies, @Organikum.

The latter will become very very wealthy very soon.

All anyone gets for GHB is hard time in the slams, it's Schedule 1. Rightly or wrongly it's Schedule 1. Alongside heroin and cocaine.

Actually we use GBL here whats perfectly legal where I live and I dont give a bloody fuck about the DEA and US laws.

From the many drugs I tried only two can be considerd as aphrodisiacs IMHO. Thats LSD and GHB/GBL. Whereby LSD is pretty harsh on erections and is prone to distraction whilst GHB/GBL worked for about 80% of all people I know who tried it. Males and females. It enhances erections, intensifies orgasm and tactile sensation not to talk that about everybody seems to get sexually attractive.
Dosage is critical though and calls for some experimenting to get to the personal optimum.

Not to forget that GHB costs me about 0,2€/gram or less

Sauron - 13-1-2007 at 09:55

Removed by Sauron for sake of decorum and preservation of the pax Polveronus.

[Edited on 13-1-2007 by Sauron]

[Edited on 14-1-2007 by Sauron]

Misanthropy - 13-1-2007 at 21:29

Sauron: I'd like to know, in 2 words or fewer please,

just what you think constitues a 'clinically' accepted aphrodisiac. You are a rather vague fellow, all previous points being considered.

GHB for (me/us/them/fuggit, several of us) meets ALL the criteria. When taken orally, (not so much IV strangely, at this point, I think due to the abrupt/crude onset perhaps?) I ease into a decidedly more sensual frame of mind. Thinking, speaking & behaving in a softer, sweeter, filthier & most definitely more sexually energetic way. My wife & our friends seem to enjoy this.

Even when alone. Even without an erection. The engagement of tactile stimulation, body wide, is highly appealing but granted, it usually leads to a raging, noticeably enhanced hardon. Especially when we bring in another person or two. :cool:

This is not just a function of hibition removal of course. The aphrodisial qualities of that alone however can be said to be relative. Not to be so offhandedly denied as 'not aphrodisiac' in nature. Who are you to say? Or anybody for that matter?

Sexual desire is in fact amplified. Physical contact is made more pleasurable. The frame of mind is most assuredly set into a profoundly pro sexual, sensual groove. The effects of this last even a few days after use, to a lesser degree, in all areas discussed. Not to mention the general, lingering feeling of well being that continues after use for that time as well.

We all fuck a lot thereafter as well, mind you.

Deeply moving, intense lovemaking tends to occur a LOT more frequently as well. The inherent difference between this and the freaky sex is assumed to be understood.

Growth hormone secretagogues may all promote that general, all over good feeling, especially when coupled with sex, so far as I know. Considering it helps us lose significant weight, promoting more & better fucking/lovemaking in the future.

The soft & filthy oral discourse alone has removed hibitions of a couple otherwise reserved/shy girls we've known. GHB not being used by them at all to get them warmed up! Freeflowing sensuality & ambition does some wonderful things!

It seems to go especially well among women; they seem to generally be more fluent in their sensual awareness than men & this magnifies that side of their nature a bit more. It's good to marry a hardcore bi-sexual woman in any case!

All this being said, I like it now with a bit of speed & a penis pump.

Oh yeah, aphrodisiacs... right... you were defining them as?

A lot of people seem to feel the same way. Results of this are evident in the field. Just look. Wikipedia isn't always the definitive answer you know & is at times misleading or at the least, lacking.

GHB: Makes me superhuman. I know this because when she's on it, my wife could fuck you dead!

Good night.

Sauron - 13-1-2007 at 21:57

I have been strongly advised to drop this topic and all related discussions of human libido enhancement due to its contentious and inflammatory nature.

I have accepted that advice from the powers that be.

Misanthropy - 13-1-2007 at 22:12

Ah, too bad. Ok.

How is it that people become so upset over things which are so natural & nice?

Anyway, I never noticed much effect from sildenafil @ ~75mg. 20 mg of Tadalafil however, was great! I didn't need either of them, but the tadalafil promoted much more blood flow into my penis than was usual. It seems to have opened things up somehow and doesn't really give as much effect as it did at first. The very first time I tried it, I got unintentional & uninstigated hard ons just from sitting on my chair! All the blood just sort of squished up into there. ?!?

There is an interesting sildenafil/tadalafil liquid mix (50mg&20mg/ml) for cheap at a site specializing in, innovative, physical development research compounds. I believe it may be found through the IBE forums...

[Edited on 14-1-2007 by Misanthropy]

Sauron - 13-1-2007 at 22:33

Agreed but apparently this one has previously erupted into flames and the gods of the forum want to avoid such pyrophoric topics. Our is not to reason why, I guess.

Misanthropy - 14-1-2007 at 00:09

It seems PT-141 is being produced in China ATM & is available.

Sauron - 14-1-2007 at 05:11

I did say that China and India are the ussual suspects in the knockoff of such things (cf Viagra).

Having purchased chemicals from China several times, I can tell you that prices are cheap, quality is highly variable and packaging is usually awful.

Misanthropy - 15-1-2007 at 15:29

Well, at $1.2K/Gram, I think I'll wait!

Sauron - 15-1-2007 at 17:50

Assuming they are selling the correct peptide that is 40 doses for $30 US each. About 3C the price of a 100 mg (multi-dose) Viagra.

Doubtless the price will come down later when they retail it and also sell in bulk as they do with sild.

This price is for the earlybirds who don't want to wait, I guess.

Sandmeyer - 15-1-2007 at 20:22

Quote:

Originally posted by Organikum
Actually we use GBL here whats perfectly legal where I live and I dont give a bloody fuck about the DEA and US laws.

Actually, I find the effects of GBL a bit "hammering", butandiole even more so, not as clean, cozy as GHB. It seems that GBL and BDO are active in their own right and not soely as a result of metabolizm into GHB. I was schocked too see that even on tolerance 2 ml GHB produced strong and longer lasting effect after 300 mg pure caffeine taken 2 hours previously to GHB. Thought I haven't repeated this combo since.

Few things can mach a saturday evening with a cute girl, candle lights and of course a 3 ml GHB dose with small boosters now and then throughout the night of intensive love-making. Only downside (or maybe not) is that orgazm is quite a body-workout to reach. Too bad GHB is illegal nowdays, so one has too rely on the legal alternatives.

I have heard from several lucky souls that grass is a good aphrodisiak, but in me it produces too overwhelming paranoia and an impression that I've gone "mad". Only time I enjoyed it was when watching Simpsons and Futurama stoned with a pot-head friend, hell of a fun.

[Edited on 16-1-2007 by Sandmeyer]

Misanthropy - 22-2-2007 at 12:10

An associate has now sequenced melanotan 2 & PT-141 (acid & amide, so I'm told.)

M2 is said to still be more active upon the libido than PT-141. Activity of PT-141 was reported as negligible at best in this person.

I've recieved samples of both & hope to compare notes in the very near future.

gregxy - 22-2-2007 at 16:59

Another drug which improves libido in older (40+) males is anastazole (arimidex). Arimidex was developed to treat breast cancer in women and binds to the aromatase enzyme blocking the conversion of testosterone to estrogen. In males, low doses of about 1mg/week increase the ratio of testosterone to estrogen which helps with both libido and body composition. Too high a dose will completely block estrogen production which is unhealthy and completely kills the libido. Some theories suggest that testosterone must convert to estrogen in the brain to be effective.

Sauron - 22-2-2007 at 20:48

There's a lot of bullshit on the net about Melanotan II

Melanotan II has no libido enhancing activity.

PT-141 now known as bremelanotide, has that.

And it is not an amide form.

It is Ac-Nle-cyclo(Asp-His-D-Phe-Arg-Trp-Lys)-OH

Melanotan II is not cyclized.

[Edited on 24-2-2007 by Sauron]

Misanthropy - 23-2-2007 at 09:25

I think he meant M2 by that. Regardless, here they sit with some analysis info sheets.

Bioassay will ensue shortly.

[Edited on 2-23-2007 by Misanthropy]

Sauron - 23-2-2007 at 22:24

My understanding is that the tanning agent development is licensed to an entirely different company, while the bremelanotide etc. is licensed to Palatine Technologies.

The libido enhancing properties were engineered out of the Melanotan II while the same were optimized in PT-141.

The grey market knockoff artists on the Net don't want you to know that, so they can scam you with ersatz melanotan II while insinuating it will do more than give you a tan. It will not.

And PT-141 won't give you a tan.

They are not spending all those millions on FDA trials for a product that does not work.

Misanthropy - 23-2-2007 at 23:05

This was not purchased. It was made. Directly, by a friend who does this for a living. This is what makes me give his opinion of the results more than internet based credit.

He didn't claim that PT-141 doesn't work. Just that it didn't work on him, whereas the M2 did. Noticeably.

Apologies for the low res pics; all I've got is a 1.3Mp camera phone, ATM. My camera died. If I can get better scans of this I will. One of these got torn up by the post office as the vial inside the envelope must've jammed up a handling machine...

Here's the M2
http://img181.imageshack.us/img181/6789/m2bl0.jpg

M2 peaks
http://img293.imageshack.us/img293/4475/m2peakswd7.jpg

PT-141
http://img137.imageshack.us/img137/5543/pt141zy4.jpg

PT-141 peaks
http://img296.imageshack.us/img296/9056/pt141peaksct9.jpg

PT-141 data 1
http://img296.imageshack.us/img296/9501/pt141tablenh6.jpg

PT-141 data 2
http://img410.imageshack.us/img410/6126/pt141table2cu8.jpg

PT-141 data 3
http://img410.imageshack.us/img410/5738/pt141stuff1ox8.jpg

PT-141 data 4
http://img241.imageshack.us/img241/2153/pt141stuff2wd0.jpg

Random IGF-1 & Phosphate Buffered Saline (just because)

http://img87.imageshack.us/img87/8459/igf1pbsfr1.jpg

[Edited on 2-24-2007 by Misanthropy]

Sauron - 24-2-2007 at 06:54

Those images are unreadable.

I don't know what your friend made, what he thinks the structures are, what dose he took of whatever it was, or how he took it. Mostly because you haven;t said.

What you did say about structures seemed a bit confused, not to mention vague.

And again, all of that "data" you attached is too out of focus to read as well as poorly exposed.

I take it your friend is a professional peptide chemist?

This compound is not easy. The Nle is hard to come by. The assembly of the chain is otherwise not too hard, but the cyclization is tricky and low yield, and the purification (desalting then HPLC) is also low yielding. Do I take it he did this on an automated synthesizer?

A few years ago ABRF did a test of its members, put out a protocol for a relatively simple oligopeptide to be assembled on automated synthesizers, all by professional peptide chemists working in institutional labs. I don't know of any amatuers with such equipment. Certainly not myself. I work by classical techniques, not SPPS.

About 50% of ABRF's members turned in samples that tyrned out to be WRONG. Half the labs botched the prep.

So let's just say that I believe there is room for doubt.

Misanthropy - 24-2-2007 at 17:30

Yes he is employed in that role. Yes, they suck; sorry about the resolution.

He does seem pretty happy with his 'M2'. Perhaps I can get him to sit under a tanning bed for 15 minutes or so to see if he changes ethnicity.

Those are pretty amazing stats. Makes me nervous to follow suit, but, what would mad science be without trying new things?

Sauron - 25-2-2007 at 06:45

I found that paper on the ABRF site last year, thought I saved it to hard disk but am having trouble locating it.

I am going to make this stuff and purify it rigorously, before I or any of my friends takes any. Which is why I have spent $40,000 on HPLC prep scale and am not finished buying it all yet. If you read the relevant patents you will see that in the examples the losses associated with the final cyclization (using DPPA) and the two chromatographic purifications were staggering.

Incidentally ask your friend where he got his L-Norleucine (Nle) as that is quite hard to find. It is an expensive internal stabdard for AA analysis. I am making my own racemic Nle and resolving it enzymatically with papain. Too expensive to buy in the quantities I want.

Misanthropy - 25-2-2007 at 09:58

I don't know these details; I'm no chemist.

Discussion of it went like this, verbatim:

vvvvvvvvvvvvvvvvvvvvvvvvvvvvvvv
no, but i did order some d-phe and nle today
-------------------
well it took a solid week to get the necessary supplies, but currently there is a nice sample being freeze dried ... i am anxious to test it out to say the least, not so much about the libido effects but for the 'insta-tan' effects, since i tan ~7 days as it is ... well, nevermind, im anxious about both it should be interesting

ended up having to do the amide form of the molecule (making it melanotan II, not pt-141) as i didnt want to purchase the expensive resin needed to make the acid form ... either way it should be ok ; synthesis was a breeze =)

i actually think the difference between acid/amide forms are that the amide gives you more of the skin tan effect, and hence for pt-141 the drug cos. decided to use the acid .... however i have been unable to find any solid literature to back that up so its all just speculation, but either way ill let you know if its all its cracked up to be ....
-------------------------

The amide molecule I made is kind of a bust. I found the patent for the Pt-141 and apparently the difference between acid and amide is that the acid is 1000x more potent at the MC-4R (the receptor that gives the sexual desire effect) and thus allow for small (mg to ug) quantities to be used for this effect. So I will be working to get the acid molecule here soon.... just need some time.

Also have you looked at the melanocortin family of receptors at all? The MC-4R is cool, but the MC-2R (also known as the adrenocorticotropic receptor - ACTHR) might be even better. MC-2R activation causes steroidogenesis through the HPA axis! I just saw that today whilst searching the net for info. So I may be hitting up some MC-2R agonist peptides in the future at some point to see what's up with this.
--------------------------------------

I did take some courses/labs on in/organic before I graduated but that's about it ... we did attempt to synthesize the "famous Ru 6-coordinated PPh3-ligand that catalyzes everything" (forget the actual name) in inorganic lab over a few weeks time. I think out of 6-7 groups, only 1 actually got it made in a working form. The entire process is very air sensitive. That would be my main worry if you do not have access to inert atmospheres. Other than that I don't have a clue.
---------------------------------
Yea so I've made them both now. The melanotan actually works pretty well as I noticed the other day that I was looking exceptionally not-like-a-white-guy after injecting it for 5-6 days in a row. However the pt-141 I am not so sure about. All it did for me was make my stomach spasm uncomfortably for ~30 minutes. The melanotan has more of the "spontaneous erection" effect I think. Final verdict has yet to be made though.
---------------------

also make sure that after you dissolve it to freeze it between use to prevent peptide degradation .... the peptide itself should be pretty stable since it has the lactam bond in it, but i have seen other linear peptides start to fall apart after 3-5 days in solution and be completely destroyed by 1 week's time

melanotan.org has lots of info in their forum ... the pt-141 patent talks about being able to snort it as a nasal spray but i dont think that works and you are better off just injecting it subcutaneously ..... you could try intravenous if you feel tempted.

^^^^^^^^^^^^^^^^^^^^^^

So that's all I know about this stuff. I know the IGF-1 was effective at least.

Best wishes on your upcoming project Sauron. It sounds like your the man in this area. Good luck! :cool:

Misanthropy - 27-2-2007 at 09:47

Regarding the Nle:
"not really sure about expensive and hard to find ... our catalogue has protected/deprotected 5g quantities for under 100$ ... the only real problem with it is that it is a sticky goo instead of powder like most amino acids are.

The other oddball amino acids needed in the synthesis are more expensive (Boc-D(Fmoc)-OH, Boc-K(Fmoc)-OH)."

Sauron - 27-2-2007 at 10:23

Everything's relative. I call $100 for 5 g expensive. For $20/g I definitely opto to make it myself. I want 100s of grams. I did get a quote from one company that does custom AA work in China, they wanted $10,000 a kilo.

The D-Phe, is cheap, a couple hundred a Kg.

All the others require side chain protection, the selection of which depends on the overall coupling strategy and influences the global deprotection protocol at the end. Things get...interesting.

At least there are no frigging sulhydryls to content with, but their is His, there is Trp, there is Lys, and there is Arg, and they are troublesome enough. Asp is not a particular hassle.

I don't do solid phase so resins are not an issue. As for overall strategy I am inclined toward Fmoc. I am a little fed up with buying Boc2O and having it turn out to be mostly tBuOH. Boc-ON is stable but costlier. I'd make my own but it requires phosgene, wich I'd really rather not work with. Same reason I stay away from Z-Cl (benzyl chloroformate.)