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-H-3] butyric acid ([H-3]GHB) and [H-3]NCS-382 from GHB receptors, on one hand, and [H-3]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 [H-3]GHB and 2 and 14 times, respectively, in displacing [H-3]NCS-382 from GHB binding. Neither RS-NCS-382 nor its enantiomers inhibited [H-3]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

Stereoselectivity of NCS-382 binding to gamma-hydroxybutyrate (GHB) receptor in the rat brain

CASTELLI, MARIA PAOLA;PISTIS, MARCO;
2002

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-H-3] butyric acid ([H-3]GHB) and [H-3]NCS-382 from GHB receptors, on one hand, and [H-3]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 [H-3]GHB and 2 and 14 times, respectively, in displacing [H-3]NCS-382 from GHB binding. Neither RS-NCS-382 nor its enantiomers inhibited [H-3]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
GAB (gamma-hydroxybutyrate) binding site; RS-NCS-382, , ; R-NCS-382; S-NCS-382; baclofen; GABA(B) receptor
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11584/4477
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