2-Phenyl-imidazo[1,2-a]pyridine compounds containing hydrophilic groups as potent and selective ligands for peripheral benzodiazepine receptors: synthesis, binding affinity and electrophysiological studies.

A series of imidazopyridine acetamides were synthesized to evaluate the effects of structural changes at both central (CBRs) and peripheral benzodiazepine receptors (PBRs). These changes include the introduction of polar substituents or ionizable functional groups at the 2- and 8-position of the imidazopyridine skeleton. The results suggest that substituents endowed with hydrogen bonding acceptor and/or donor properties in the para position of the phenyl ring lead to high affinity for PBR. In electrophysiological studies, it was found that compounds 9, 12, 13, and 28 markedly enhanced GABA-evoked Cl (-) currents in Xenopus oocytes expressing alpha 1beta 2gamma 2 GABA A receptors. The capability of flumazenil to reduce the stimulatory effect exerted by compound 9 supports the conclusion that the modulatory effects of the examined compounds occur involving the CBR. The ability of compound 16 to increase GABA A receptor-mediated miniature inhibitory postsynaptic currents in CA1 pyramidal neurons is indicative of its ability to stimulate the local synthesis and secretion of neurosteroids.