Novel 2-phenylimidazo[1,2-a]pyridine derivatives as potent and selective ligands for peripheral benzodiazepine receptors: Synthesis, binding affinity, and in vivo studies

The substituent effects at positions 6 and 8 (compounds 17-31) as well as a t the amide nitrogen (compounds 32-40) of a series of 2-phenylimidazo[1,2-a ]pyridineacetamides were evaluated at both central (CBR) and peripheral (PB R) benzodiazepine receptors. The structure-activity relationship studies de tailed herein indicate the key structural features required for high affini ty and selectivity for PER, Substitution on the imidazopyridine nucleus at position 8 with lipophilic substituents and the presence of one chlorine at om at the para position of the phenyl ring at C(2) are crucial features for high binding affinity and selectivity toward PER. A small subset of active ligands (i.e., 17, 20, 26, 34, and 35) were evaluated in vitro in Xenopus oocytes expressing cloned human GABAA receptors for their effects at CBR an d in vivo for their ability to stimulate the synthesis of neurosteroids suc h as pregnenolone, progesterone, allopregnanolone, and allotetrahydrodeoxyc orticosterone (THDOC). Compounds 17, 20, 26, and 34 markedly increased the levels of neuroactive steroids in plasma and cerebral cortex, unlike compou nd 35.