Differential potentiation of GABA A receptor function by two stereoisomers of diimidazoquinazoline analogues

1 U‐84935, diimidazo[1,5‐a;1′,2′‐C]quinazoline,5‐(5‐cyclopropyl‐1,2,4‐oxidiazol‐3yl)‐2,3‐dihydro, is a ligand of high affinity for the benzodiazepine site of the GABA A receptor composed of α 1 β 2 γ 2 subunits. 2 The efficacy of its analogues was measured with their ability to potentiate GABA‐mediated Cl − currents in the whole cell configuration of the patch clamp techniques in human kidney cells (A293 cells) expressing the subtype of the GABA A receptor. 3 The analogues displayed various levels of efficacy including agonists, partial agonists and antagonists without marked changes in their affinity for the receptors. 4 The major determinant of their efficacy was the spacial configuration of a methyl substituent of the C2 atom of the rigid and planar diimidazoquinazoline ring: U‐90167, containing the methyl substituent projected below the plane of the ring, markedly enhanced the GABA current with a maximal potentiation of 220 ± 25%, while its stereoisomer, U‐90168, marginally increased the GABA response with a maximal potentiation of 45 ± 10%, to which its methyl group appeared to contribute very little. 5 U‐90167 potentiated the GABA response with an EC 50 of 8.1 n m and a Hill coefficient of 1.1 and did not alter the reversal potential for the Cl − current. 6 From computational modelling, the sensitive methyl group of U‐90167 could be assigned to the general region for the 5‐phenyl group of diazepam. The diimidazoquinazoline, because of its rigid and plantar ring structure, may be useful to define further the out‐of‐plane region responsible for agonistic activity and to pinpoint other areas pivotal to the functionality of benzodiazepine ligands.