3-PHENYL-SUBSTITUTED IMIDAZO[1,5-A]QUINOXALIN-4-ONES AND IMIDAZO[1,5-A]QUINOXALINE UREAS THAT HAVE HIGH-AFFINITY AT THE GABA(A) BENZODIAZEPINE RECEPTOR COMPLEX/

A series of imidazo[1,5-alpha]quinoxalin-4-ones and imidazo[1,5-alpha] quinoxaline ureas containing substituted phenyl groups at the 3-positi on was developed. Compounds within the imidazo-[1,5-alpha]quinoxaline urea series had high affinity for the GABA(A)/benzodiazepine receptor complex with varying in vitro efficacy, although most analogs were par tial agonists as indicated by [S-35]TBPS and Cl- current ratios. Inter estingly, a subseries of piperazine ureas was identified which had bip hasic efficacy, becoming more antagonistic with increasing concentrati on. Analogs within the imidazo [1,5-alpha] quinoxalin-4-one series had substantially decreased binding affinity as compared to the quinoxali ne urea series. These compounds ranged from antagonists to full agonis ts by in. vitro analysis, with several derivatives having roughly 4-fo ld greater intrinsic activity than diazepam as indicated by Cl- curren t measurement. Numerous compounds from both series were effective in a ntagonizing metrazole-induced seizures, consistent with anti-convulsan t properties and possible anxiolytic activity. Most of the quinoxaline ureas and quinoxalin-4-ones were active in an acute electroshock phys ical dependence side effect assay in mice precluding further developme nt.