Unsaturated phosphinic analogues of γ-aminobutyric acid as GABA C receptor antagonists

Abstract

The phosphinic and methylphosphinic analogues of γ-aminobutyric acid (GABA) are potent GABA C receptor antagonists but are even more potent as GABA B receptor agonists. Conformationally restricted unsaturated phosphinic and methylphosphinic analogues of GABA and some potent GABA B receptor phosphonoamino acid antagonists were tested on GABA C receptors in Xenopus oocytes expressing human retinal ϱ 1 mRNA. 3-Aminopropyl- n-butyl-phosphinic acid (CGP36742), an orally active GABA B receptor antagonist, was found to be a moderately potent GABA C receptor antagonist (IC 50 = 62 μM). The unsaturated methylphosphinic and phosphinic analogues of GABA were competitive antagonists of the GABA C receptors, the order of potency being [( E)-3-aminopropen-1-yl]methyl-phosphinic acid (CGP44530, IC 50 = 5.53 μM) > [( E)-3-aminopropen-1-yl]phosphinic acid (CGP38593, IC 50 = 7.68 μM) > [( Z)-3-aminopropen-1-yl]methylphosphinic acid (CGP70523, IC 50 = 38.94 μM) > [( Z)-3-aminopropen-1-yl]phosphinic acid (CGP70522, IC 50 > 100 μM). This order of potency differs from that reported for these compounds as GABA B receptor agonists, where the phosphinic acids are more potent than the corresponding methylphosphinic acids.