Hydroxy-1,2,5-oxadiazolyl Moiety as Bioisoster of the Carboxy Function. Synthesis, Ionization Constants, and Pharmacological Characterization of γ-Aminobutyric Acid (GABA) Related Compounds

Three 4-substituted 1,2,5-oxadiazol-3-ols containing aminoalkyl substituents (analogues and homologues of γ-aminobutyric acid (GABA)) were synthesized to investigate the hydroxy-1,2,5-oxadiazolyl moiety as a bioisoster for a carboxyl group at GABA receptors. The pKa values of the target compounds were close to those of GABA. At GABAA receptors of cultured cerebral cortical neurons, weak agonist and partial agonist profiles were identified, demonstrating the 4-hydroxy-1,2,5-oxadiazol-3-yl unit to be a nonclassical carboxyl group bioisoster.