Potent GHB analogs
With all that's been posted here about GHB there should be some interest in these unsaturated cyclic analogs that are many times more potent than GHB
& don't even look very similar to GHB itself:
| Quote: | J Pharmacol Exp Ther. 2005 Oct;315(1):346-51. Epub 2005 Jul 12.
Novel cyclic gamma-hydroxybutyrate (GHB) analogs with high affinity and stereoselectivity of binding to GHB sites in rat brain.
Wellendorph P, Høg S, Greenwood JR, de Lichtenberg A, Nielsen B, Frølund B, Brehm L, Clausen RP, Bräuner-Osborne H.
Department of Medicinal Chemistry, The Danish University of Pharmaceutical Sciences, Copenhagen, Denmark.
Gamma-hydroxybutyrate (GHB) is a psychotropic compound endogenous to the brain. Despite its potentially great physiological significance, its
exact molecular mechanism of action is unknown. GHB is a weak agonist at GABA(B) receptors, but there is also evidence of specific GHB receptor sites,
the molecular cloning of which remains a challenge. Ligands with high affinity and specificity for the reported GHB binding site are needed for
pharmacological dissection of the GHB and GABA(B) effects and for mapping the structural requirements of the GHB receptor-ligand interactions. For
this purpose, we have synthesized and assayed three conformationally restricted GHB analogs for binding against the GHB-specific ligand [3H]NCS-382
[(E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene-)acetic acid] in rat brain homogenate. The cyclohexene and cyclopentene
analogs, 3-hydroxycyclohex-1-enecarboxylic acid [(RS)-HOCHCA] and 3-hydroxycyclopent-1-enecarboxylic acid [(RS)-HOCPCA], were found to be
high-affinity GHB ligands, with IC50 values in the nanomolar range, and had 9 and 27 times, respectively, higher affinity than GHB. The
stereo-selectively synthesized R,R-isomer of the trans-cyclopropyl GHB analog, HOCPrCA, proved to have 10-fold higher affinity than its enantiomer.
Likewise, the R-enantiomers of HOCHCA and HOCPCA selectively inhibited [3H]NCS-382 binding. The best inhibitor of these, (R)-HOCPCA, has an affinity
39 times higher than GHB and is thus among the best GHB ligands reported to date. Neither of the cycloalkenes showed any affinity (IC50 > 1 mM) for
GABA(A) or GABA(B) receptors. These compounds show excellent potential as lead structures and novel tools for studying specific GHB receptor-mediated
pharmacology.
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The pdf of this paper can be found here: http://jpet.aspetjournals.org/cgi/reprint/315/1/346. The double bonds are likely optional but are probably linked to the potency reported. There
is none present in the cyclopropyl analog, 2-(hydroxymethyl)cyclopropanecarboxylic acid.
The synthesis scheme for the C5 & C6 molecules can be found here: http://jpet.aspetjournals.org/cgi/data/jpet.105.090472/DC1/2. Starting materials for the multi-step syntheses are ethyl
2-oxocyclopentanecarboxylate & ethyl 2-oxocyclohexanecarboxylate (see http://www.orgsyn.org/orgsyn/pdfs/CV7P0351.pdf for synthesis from cyclohexanone via Claisen condensation with dimethyl carbonate). First step is
reduction of the carbonyl group with NaBH4 followed by dehyderation to get to the alpha,beta-unsaturated cyclic esters. CrO3 was then used to
get the 3-keto derivatives via allylic oxidation. The racemic allylic alcohol-esters were obtained by selective reduction with NaBH4.CeCl3 followed
by saponification with aq. Na2CO3. (The Experimental Details is a .doc file at the same url).
[Edited on 6-7-2008 by Ritter]
[Edited on 6-7-2008 by Ritter]
Ritter
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\"The production of too many useful things results in too many useless people.\"
Karl Marx
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