| Abstract
| - A series of imidazo[1,5-a]quinoxaline piperazine ureas appended with a tert-butyl ester sidechain at the 3-position was developed. Analogues within this series have high affinity for theγ-aminobutyric acid A (GABAA)/benzodiazepine receptor complex with efficacies ranging frominverse agonists to full agonists. Many analogues were found to be partial agonists as indicatedby [35S]TBPS and Cl- current ratios. Uniquely, a number of these analogues were found tohave a bell-shaped dose−response profile in the α1β2γ2 subtype as determined by whole cellpatch-clamp technique, where in vitro efficacy was found to decrease with increasing drugconcentration. Many of the compounds from this series were effective in antagonizing metrazole-induced seizures, consistent with anticonvulsant and possibly anxiolytic activity. Additionally,several analogues were also effective in lowering cGMP levels (to control values) after appliedstress, also consistent with anxiolytic-like properties. The most effective compounds in thesescreens were also active in animal models of anxiety such as the Vogel and Geller assays. Theuse of the piperazine substituent allowed for excellent drug levels and a long duration of actionin the central nervous system for many of the quinoxalines, as determined by ex vivo assay.Pharmacokinetic analysis of several compounds indicated excellent oral bioavailability and areasonable half-life in rats. From this series emerged two partial agonists (55, 91) which hadgood activity in anxiolytic models, acceptable pharmacokinetics, and minimal benzodiazepine-type side effects.
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