Stereoselectivity of NCS-382 binding to gamma-hydroxybutyrate receptor in the rat brain.

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Castelli MP, Mocci I, Pistis M, Peis M, Berta D, Gelain A, Gessa GL, Cignarella G

Stereoselectivity of NCS-382 binding to gamma-hydroxybutyrate receptor in the rat brain.

Eur J Pharmacol. 2002 Jun 20;446(1-3):1-5.

PubMed ID

12098579 [ View in PubMed

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Abstract

gamma-Hydroxybutyric acid (GHB), a naturally occurring metabolite of gamma-aminobutyric acid (GABA), has been postulated to act both as a specific agonist of GHB receptors and as a weak GABA(B) receptor agonist. The racemic compound 6,7,8,9-tetrahydro-5-hydroxy-5H-benzocyclohept-6-ylideneacetic acid (RS-NCS-382), the only available antagonist of GHB receptors, has been resolved in two enantiomers, R- and S-; the potency of the latter to displace 4-hydroxy [2-3-(3)H] butyric acid ([(3)H]GHB) and [(3)H]NCS-382 from GHB receptors, on one hand, and [(3)H]baclofen from GABA(B) receptors on the other was compared in rat brain homogenates. R-NCS-382 was found to be twice and 60 times more potent than the RS- and S-forms, respectively, in displacing [(3)H]GHB and 2 and 14 times, respectively, in displacing [(3)H]NCS-382 from GHB binding. Neither RS-NCS-382 nor its enantiomers inhibited [(3)H]baclofen binding up to a concentration of 1 mM. Our results demonstrate that R-NCS-382 is the enantiomer of RS-NCS-382 with higher affinity for GHB receptors.

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Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
gamma-Hydroxybutyric acid	Gamma-hydroxybutyrate (GHB) receptor	Protein	Humans	Yes	Agonist	Details