Phosphinic, phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABA C receptor antagonists

Abstract

A number of amino acids bioisosterically derived from the specific GABA A agonist, isonipecotic acid, were electrophysiologically characterized as antagonists at GABA C ρ 1 receptors expressed in Xenopus oocytes. The phosphinic acid analogue of isonipecotic acid, piperidin-4-ylphosphinic acid ( 2), was comparable with the standard GABA C antagonist, (1,2,5,6-tetrahydropyridin-4-yl)methylphosphinic acid (TPMPA), in terms of potency and GABA C versus GABA A receptor selectivity. Whereas the phosphonic acid analogue, piperidin-4-ylphosphonic acid ( 4), was at least an order of magnitude weaker than piperidin-4-ylphosphinic acid as a GABA C antagonist, the seleninic acid analogue, piperidin-4-ylseleninic acid (SEPI, 6), was the most potent and selective GABA C antagonist within the group of isonipecotic acid derived amino acids studied.