title: Stereoselectivity of NCS-382 binding to gamma-hydroxybutyrate receptor in the rat brain.
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.
authors.affiliation: Neuroscienze S.c.a r.l., Via Palabanda 9, I-09123, Cagliari, Italy. castelli@unica.it
authors.forename: M Paola
authors.initials: MP
authors.lastname: Castelli
authors.forename: Ignazia
authors.initials: I
authors.lastname: Mocci
authors.forename: Marco
authors.initials: M
authors.lastname: Pistis
authors.forename: Michela
authors.initials: M
authors.lastname: Peis
authors.forename: Daniela
authors.initials: D
authors.lastname: Berta
authors.forename: Arianna
authors.initials: A
authors.lastname: Gelain
authors.forename: Gian Luigi
authors.initials: GL
authors.lastname: Gessa
authors.forename: Giorgio
authors.initials: G
authors.lastname: Cignarella
mesh_terms: D000818:Animals; D001567:Benzocycloheptenes / Q000737:chemistry / Q000378:metabolism*; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism*; D058786:GABA-B Receptor Agonists; D066298:In Vitro Techniques; D008566:Membranes; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011956:Receptors, Cell Surface / Q000819:agonists / Q000378:metabolism*; D013237:Stereoisomerism
chemical_list: C039403:4-hydroxybutyric acid receptor; D001567:Benzocycloheptenes; D058786:GABA-B Receptor Agonists; D011956:Receptors, Cell Surface; C066471:NCS 382