PHOSPHINIC ACID ANALOGS OF GABA .1. NEW POTENT AND SELECTIVE GABA(B) AGONISTS

The antispastic agent and muscle relaxant baclofen 1 is a potent and s elective agonist for bicuculline-insensitive GABA(B) receptors. For ma ny years efforts to obtain superior GABA(B) agonists were unsuccessful . We describe the syntheses and biological properties of two new serie s of GABA(B) agonists, the best compounds of which are more potent tha n baclofen in vitro and in vivo. They were obtained by replacing the c arboxylic acid group of GABA or baclofen derivatives with either the p hosphinic acid or the methylphosphinic acid residue. Surprisingly, eth yl- and higher alkylphosphinic acid derivatives of GABA yielded novel GABA(B) antagonists, which are described in part 2 of this series. Str ucture-activity relationships of the novel GABA(B) agonists are discus sed with respect to their affinities to GABA(B) receptors as well as t o their effects in many functional tests in, vitro and in vivo providi ng new muscle relaxant drugs with significantly improved side effect p rofiles.