UNSATURATED PHOSPHINIC ANALOGS OF GAMMA-AMINOBUTYRIC-ACID AS GABA(C) RECEPTOR ANTAGONISTS

The phosphinic and methylphosphinic analogues of gamma-aminobutyric ac id (GABA) are potent GABA(C) receptor antagonists but are even more po tent as GABA(B) receptor agonists. Conformationally restricted unsatur ated 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 GAB A(B) receptor antagonist, was found to be a moderately potent GABA(C) receptor antagonists (IC50 = 62 mu M). The unsaturated methylphosphini c 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)-aminoprope n-1-yl]phosphinic acid (CGP38593, IC50 = 7.68 mu M) > [(Z)-3-aminoprop en-1-yl]methylphosphinic acid (CGP70523, IC50 = 38.94 mu M) > [Z)-3-am inopropen-1-yl]phosphinic acid (CGP70522, IC50 > 100 mu M). This order of potency differs from that reported for these compounds GABA(B) rec eptor agonists, where the phosphinic acids are more potent than the co rresponding methylphosphinic acids. (C) 1997 Elsevier Science B.V.