Novel GHB analogs with high affinity to GHB receptors

[JacksinPA]

GHB analogs with journal article reference:

http://jpet.aspetjournals.org/content/jpet/315/1/346.full.pdf

"Ligands with high affinityand specificity for the reported GHB binding site are needed forpharmacological dissection of the GHB and GABAB effects andfor mapping the structural requirements of the GHB receptorligandinteractions. For this purpose, we have synthesized andassayed three conformationally restricted GHB analogs forbinding against the GHB-specific ligand [3H]NCS-382 [(E,RS)-(6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylidene)aceticacid] in rat brain homogenate.

The cyclohexene andcyclopentene analogs, 3-hydroxycyclohex-1-enecarboxylicacid [(RS)-HOCHCA] and 3-hydroxycyclopent-1-enecarboxylicacid [(RS)-HOCPCA], were found to be high-affinity GHB ligands,with IC50 values in the nanomolar range, and had 9 and27 times, respectively, higher affinity than GHB.

The stereoselectivelysynthesized R,R-isomer of the trans-cyclopropylGHB analog, HOCPrCA, proved to have 10-fold higher affinitythan its enantiomer. Likewise, the R-enantiomers of HOCHCAand HOCPCA selectively inhibited [3H]NCS-382 binding. Thebest inhibitor of these, (R)-HOCPCA, has an affinity 39 timeshigher than GHB and is thus among the best GHB ligandsreported to date.

Neither of the cycloalkenes showed any affinity(IC50 1 mM) for GABAA or GABAB receptors. Thesecompounds show excellent potential as lead structures andnovel tools for studying specific GHB receptor-mediated pharmacology."

 

[Limpet_Chicken]

Lets just hope that nobody takes after these looking for a GHB-esque recreational. (it wouldn't be, GHBr agonism in the case of GHB is ameliorated in the ability to cause frank neurotoxic effects due to GABAb agonism inhibiting glutamate release caused by activation of GHB receptors)

GHB receptors cause glutamate release, which would result in convulsant action and excitotoxicity mediated via NMDARs, AMPARs and KARs all, not to mention potential trouble from metabotropic glutamate receptor activation, although thats less clear cut. Still it wouldn't be a good idea to take these, folks, just putting it out there.

 

[Wiserthanearlier]

Is GHB such an anomaly?

Why would it be that exploration of the above is so close to dangerous territory with convulsing the major concern?
Is the action of GHB such a fluke?

I dont have any pharmacological background, just wonder why the above post is shot down so quickly

 

[Pomzazed]

^
Do you want to directly induce excitotoxicity?....