A Review of Pharmacology of NCS‐382, a Putative Antagonist of γ‐Hydroxybutyric Acid (GHB) Receptor

Abstract

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.

γ-Aminobutyric AcidB (GABAB)-Receptor Mediation of Different In Vivo Effects of γ-Butyrolactone

“…Taken together, these results suggest that the specific-GHB binding site contributes minimally to the above effects of GHB and its precursors. Alternatively, it can be hypothesized that NCS-382 may not be particularly selective for the specific-GHB binding site (15) or even possess agonistic properties at this binding site (28), leaving the contribution of this binding site on GHB, 1,4-BD, and GBL pharmacology an open issue. Accordingly, it is worthy of note that the recently cloned specific-GHB binding site was insensitive to NCS-382, suggesting the possible existence of different subtypes of this binding site (29).…”

“…Different lines of experimental evidence suggest the existence of a second GHB site of action, represented by a specific-GHB binding site (1,14). In order to evaluate the possible contribution of this substrate to the above GBL effects, the present study also included a series of experiments with NCS-382, a putative antagonist of the specific-GHB binding site (15).…”

Extrasynaptic site of action for γ-hydroxybutyrate

“…This appears unlikely, however, because in vivo studies with NCS-382 suggest that it interacts with a functional receptor; that is, NCS-382 administration diminishes the sedative and cataleptic effects of GHB and blocks the enhancing effects on the spontaneous firing rate of cortical neurons at low doses of GHB but not the depressant effects seen at higher doses (14,15). Because NCS-382 administration blocks neither GHB-induced ataxia nor its depressant effects on locomotor activity, learned and unlearned behavior, and operant responses (16,17), these actions are probably mediated by GHB activation of GABA B receptors.…”

Novel Cyclic γ-Hydroxybutyrate (GHB) Analogs with High Affinity and Stereoselectivity of Binding to GHB Sites in Rat Brain

“…In further support of this view, brains from GABA B(1) receptor knock-out mice still exhibit [ 3 H]GHB binding (Kaupmann et al, 2003;Wu et al, 2004), demon-strating that GHB and GABA binding sites are separate entities. NCS-382, a synthetic structural analog of GHB and a purported antagonist of the GHB receptor (Castelli et al, 2004), has been shown to compete with [ 3 H]GHB for the high-affinity sites. Radioligand binding studies have demonstrated [ 3 H]NCS-382 to be selective for GHB binding sites, making it a valuable tool for probing the putative GHB receptor (Mehta et al, 2001).…”