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

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