SYNTHESIS AND BINDING-AFFINITY OF 2-PHENYLIMIDAZO[1,2-A]PYRIDINE DERIVATIVES FOR BOTH CENTRAL AND PERIPHERAL BENZODIAZEPINE RECEPTORS - A NEW SERIES OF HIGH-AFFINITY AND SELECTIVE LIGANDS FOR THE PERIPHERAL-TYPE

A number of 6-substituted or 6,8-disubstituted alkyl 2-phenylimidazo[1 ,2-a]pyridine-3-carboxylates 5a-h, -acetates 5i-s, 6a-g, and -propiona tes 5t, 6h and of lkyl-2-phenylimidazo[1,2-a]pyridine-3-carboxamides 7 a-d, -acetamides 7e-t or -propionamide 7u were prepared following new synthetic methods, and their affinities for both the central (CBR) and the peripheral (PER) benzodiazepine receptors evaluated; The compound s of the ester series displayed low affinity for both receptor types. Conversely, most of lkyl(2-phenylimidazo[l,2-a]pyridin-3-yl)acetamides 7e-t proved to possess high affinity and selectivity for CBR or PBR d epending on the nature of substituents at C(6)- and/or C(8) on the het erocyclic ring system. In particular, the 6-substituted compounds 7f-n displayed ratios of IC50 values (IC50(CBR)/IC50(PBR)) ranging from 0. 32 (7m) to 232 (7k), while the 6,8-disubstituted compounds 7o-t were m ore than 1000-fold more selective for PBR versus CBR. Compounds 7f,m w ere examined in several different benzodiazepine receptor subtypes. Ex pression of specific GABAA receptor subunit assemblies in Xenopus oocy tes was utilized to evaluate functionally both the efficacy and potenc y of the positive modulation of GABA-evoked Cl- currents by 7f and 7m in comparison with Zolpidem. The rank order of potencies of these drug s was 7f (EC50 = 3.2 x 10(-8) M) > Zolpidem (EC50 = 3.6 x 10(-8) M) > 7m (EC50 = 2.2 x 10(-7) M). The actions of these compounds were also t ested on alpha(2) beta(2) gamma(2s) receptors. However, the EC50 of th ese compounds was increased, compared to alpha(1) beta(2) gamma(2s), r eceptors, by 30-, 4-, and 5-fold for 7m, 7f, and Zolpidem, respectivel y. Finally, these compounds were almost completely devoid of activity at receptors containing the alpha(5) subunit.