Gamma-hydroxybutyric acid (GHB), a naturally occurring metabolite of
gamma-aminobutyric acid (
GABA), has been postulated to act as a specific agonist of GHB receptors and as well as a weak
GABA(B) receptor agonist. To date, 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic
acid (NCS-382), a semirigid compound structurally related to GHB, is the only compound reported to be an antagonist of the GHB receptor sites. In this article we review the in vivo and in vitro pharmacological properties of
NCS-382 and its interaction with GHB and
GABA(B) receptors. Binding studies have demonstrated that
NCS-382 is a stereoselective
ligand for GHB-binding sites, with both, the high and the low component of population, showing the same distribution of GHB receptors. Indeed, this compound did not display affinity for
GABA(A),
GABA(B), or any other known receptors, while conflicting data have been reported as to its selective antagonist action at GHB receptor. Only a few studies have shown that
NCS-382 antagonizes GHB-induced effect, but a re-evaluation of all data reported in the literature suggests that the antagonistic effect of this compound could be due to an indirect action at
GABA(B) receptors. As revealed by several behavioral studies,
NCS-382 fails to antagonize GHB discriminative stimuli, GHB-induced inhibition of locomotor activity and
ataxia or suppression of operant responses. Moreover, it is capable of either eliciting qualitatively similar effects to those of GHB or enhancing some actions of GHB. In addition, the NCS-382-sensitive electrophysiological effects of endogenous and exogenous GHB observed in vivo have not been completely replicated in vitro. The only electrophysiological action of GHB antagonized in vitro by
NCS-382 required a previous blockade of
GABA(B) receptors. We concluded that
NCS-382 is a good
ligand but not a selective antagonist for GHB receptor.