DIFFERENTIAL POTENTIATION OF GABA-A-RECEPTOR FUNCTION BY 2 STEREOISOMERS OF DIIMIDAZOQUINAZOLINE ANALOGS

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 alpha1beta2gamma2 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 EC50 of 8.1 nm 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.