Selective γ‐hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of γ‐hydroxybutyric acid

Castelli, Paola; Ferraro, Luca; Mocci, Ignazia; Carta, Francesca; Carai, Mauro A.M.; Antonelli, Tiziana; Tanganelli, Sergio; Cignarella, T. Giorgio; Gessa, Gian Luigi

doi:10.1046/j.1471-4159.2003.02037.x

Cited by 67 publications

(49 citation statements)

References 37 publications

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“…However, GHB effect was found to be rather modest; a maximal stimulation of about 40 and 30% of GTPãS binding produced by GHB at 1 mM. This effect, in contrast with Snead's (63) data, was suppressed by the GABA B antagonist CGP 35348, but not by NCS-382, indicating that GHB weakly activates a G protein coupled to GABA B and not to GHB receptor (20). In both studies NCS-382 alone did not affect [ 35 S]GTPãS binding.…”

Section: Second Messengers Studiesmentioning

confidence: 61%

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

et al. 2004

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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.

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Section: Second Messengers Studiesmentioning

confidence: 61%

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

et al. 2004

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“…In this context, it will be necessary to determine the intrinsic activity of the compounds. Although isolated reports of functional assays have been described in the literature (Castelli et al, 2003;Kemmel et al, 2003;Brancucci et al, 2004), these remain to be validated by other laboratories. The compounds are also ideal lead structures, presenting ample opportunity for further substitution and structural elaboration, again with the advantage of low molecular weight and high binding efficiency of the scaffolds, bearing in mind that the synthesis of a radioligand with high specific activity could greatly aid in the molecular cloning of the GHB receptor or lay the way for tomography studies.…”

Section: Discussionmentioning

confidence: 99%

“…GHB has been shown to be a low-affinity (Mathivet et al, 1997) weak partial agonist at GABA B receptors (Lingenhoehl et al, 1999) and may also be converted into GABA in vivo and thus affect GABA receptors indirectly (Hechler et al, 1997). However, based on recent data, it would also seem that specific GHB receptor-mediated effects exist (Castelli et al, 2003;Kemmel et al, 2003;Brancucci et al, 2004). This, in combination with the presence of high-affinity [ 3 H]GHB binding sites in the brain (Benavides et al, 1982), suggests the existence of a distinct GHB receptor.…”

mentioning

confidence: 99%

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

Wellendorph¹,

Høg²,

Greenwood³

et al. 2005

J Pharmacol Exp Ther

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␥-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 receptorligand interactions. For this purpose, we have synthesized and assayed three conformationally restricted GHB analogs for binding against the GHB-specific ligand [3 H]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 IC 50 values in the nanomolar range, and had 9 and 27 times, respectively, higher affinity than GHB. The stereoselectively 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 [3 H]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 (IC 50 Ͼ 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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“…Due to GHB's widespread presence throughout the human body and brain, it is unclear as to the exact role of GHB within mammalian physiology, and a thorough-going pharmacological profile is still incomplete. At low doses, GHB has excitatory effects via its action at GHB receptors and indirect actions on extracellular glutamate concentrations (Castelli et al, 2003). However, when consumed in larger quantities, it can have extreme sedative-like effects, resulting in amnesia and unconsciousness, which have been attributed to its effects at GABA B receptors.…”

Section: The Case Of Gamma Hydroxybutyric Acid (Ghb)mentioning

confidence: 99%

Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies

Gauvin

Zimmermann

Baird

2015

Regulatory Toxicology and Pharmacology

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Selective γ‐hydroxybutyric acid receptor ligands increase extracellular glutamate in the hippocampus, but fail to activate G protein and to produce the sedative/hypnotic effect of γ‐hydroxybutyric acid

Cited by 67 publications

References 37 publications

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

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

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

Preclinical assessment of abuse liability of biologics: In defense of current regulatory control policies

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