CHARACTERIZATION OF U-101017 AS A GABA(A) RECEPTOR-LIGAND OF DUAL FUNCTIONALITY

Drugs acting on the benzodiazepine site of GABA(A) receptors are much safer than barbiturates, but are still liable to abuse. Recently, we h ave reported that a benzodiazepine site agonist, U-97775 (a dihydroimi dazoquinoxaline analog), may have minimal abuse liability because of i ts interaction with a second, low-affinity site on GABA(A) receptors, the occupancy of which, at high drug concentrations, leads to a revers al of its agonistic activity on the benzodiazepine site and inhibition of GABA-induced Cl- currents [Br. J. Pharmacol. 115 (1995) 19-24]. He re we report that U-101017 ine)carbonyl]imidazo[1,5a]quinoline-3-carbo xylate) is another similar benzodiazepine site agonist possessing the ability to reverse its agonistic activity at higher concentrations, bu t its ability to inhibit GABA currents is considerably milder than tha t of U-97775. In the alpha 6 beta 2 gamma 2 subtype where these drugs have no agonistic activity, for instance, U-101017 at concentrations u p to 80 mu M, showed no appreciable effect on GABA currents, whereas U -97775 inhibited the currents with an IC50 value of 10 mu M as measure d with the whole cell patch clamp techniques in human embryonic kidney cells expressing recombinant receptors. Similar, milder inhibition of GABA currents by U-101017 was observed in the alpha 1 beta 2 gamma 2 and alpha 3 beta 2 gamma 2 subtypes. Furthermore, U-101017 was of high er efficacy in the alpha 1 beta 2 gamma 2 than alpha 3 beta 2 gamma 2 subtypes as compared to diazepam, although its binding affinity was no t appreciably different in the two subtypes. We conclude that U-101017 is a partial benzodiazepine agonist, somewhat selective to the alpha 1 beta 2 gamma 2 subtype, and with the ability to limit its own agonis tic activity over a wide range of doses through its interaction with t he low affinity site, but without potential convulsant activity, inher ent to agents which block GABA currents.