PT  - JOURNAL ARTICLE
AU  - Petrine Wellendorph
AU  - Signe Høg
AU  - Jeremy R. Greenwood
AU  - Anne de Lichtenberg
AU  - Birgitte Nielsen
AU  - Bente Frølund
AU  - Lotte Brehm
AU  - Rasmus P. Clausen
AU  - Hans Bräuner-Osborne
TI  - Novel Cyclic γ-Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain
AID  - 10.1124/jpet.105.090472
DP  - 2005 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 346--351
VI  - 315
IP  - 1
4099  - http://jpet.aspetjournals.org/content/315/1/346.short
4100  - http://jpet.aspetjournals.org/content/315/1/346.full
SO  - J Pharmacol Exp Ther2005 Oct 01; 315
AB  - γ-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 GABAB 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 GABAB 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 GABAA or GABAB receptors. These compounds show excellent potential as lead structures and novel tools for studying specific GHB receptor-mediated pharmacology. The American Society for Pharmacology and Experimental Therapeutics