Unsaturated phosphinic analogues of gamma-aminobutyric acid as GABA(C) receptor antagonists

The phosphinic and methylphosphinic analogues of gamma-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 rho(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 antagonists (IC50 = 62 mu M). 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, IC50 = 5.53 mu M) > [(E)-aminopropen-1-yl]phosphinic acid (CGP38593, IC50 = 7.68 mu M) > [(Z)-3-aminopropen-1-yl]methylphosphinic acid (CGP70523, IC50 = 38.94 mu M) > [Z)-3-aminopropen-1-yl]phosphinic acid (CGP70522, IC50 > 100 mu M). This order of potency differs from that reported for these compounds GABA(B) receptor agonists, where the phosphinic acids are more potent than the corresponding methylphosphinic acids. (C) 1997 Elsevier Science B.V.