Piperazine imidazo[1,5-a]quinoxaline ureas as high-affinity GABA(A) ligands of dual functionality

A series of imidazo[1,5-alpha]quinoxaline piperazine ureas appended with a tert-butyl ester side chain at the 3-position was developed. Analogues with in this series have high affinity for the gamma-aminobutyric acid A (GABA(A ))/benzodiazepine receptor complex with efficacies ranging from inverse ago nists to full agonists. Many analogues were found to be partial agonists as indicated by [S-35]TBPS and Cl- current ratios. Uniquely, a number of thes e analogues were found to have a bell-shaped dose-response profile in the a lpha(1)beta(2)gamma(2) subtype as determined by whole cell patch-clamp tech nique, where in vitro efficacy was found to decrease with increasing drug c oncentration. Many of the compounds from this series were effective in anta gonizing metrazole-induced seizures, consistent with anticonvulsant and pos sibly anxiolytic activity. Additionally, several analogues were also effect ive in lowering cGMP levels (to control values) after applied stress, also consistent with anxiolytic-like properties. The most effective compounds in these screens were also active in animal models of anxiety such as the Vog el and Geller assays. The use of the piperazine substituent allowed for exc ellent drug levels and a long duration of action in the central nervous sys tem for many of the quinoxalines, as determined by ex vivo assay. Pharmacok inetic analysis of several compounds indicated excellent oral bioavailabili ty and a reasonable half-life in rats. From this series emerged two partial agonists (55, 91) which had good activity in anxiolytic models, acceptable pharmacokinetics, and minimal benzodiazepine-type side effects.