Characterization of U-101017 as a GABA A receptor ligand of dual functionality

Abstract

Drugs acting on the benzodiazepine site of GABA A receptors are much safer than barbiturates, but are still liable to abuse. Recently, we have reported that a benzodiazepine site agonist, U-97775 (a dihydroimidazoquinoxaline analog), may have minimal abuse liability because of its interaction with a second, low-affinity site on GABAA receptors, the occupancy of which, at high drug concentrations, leads to a reversal of its agonistic activity on the benzodiazepine site and inhibition of GABA-induced Cl − currents [ Br. J. Pharmacol. 115 (1995) 19–24]. Here we report that U-101017 (7-chloro-5[ cis-3,5-dimethylpiperazine)carbonyl]imidazo[1,5a]quinoline-3-carboxylate) is another similar benzodiazepine site agonist possessing the ability to reverse its agonistic activity at higher concentrations, but its ability to inhibit GABA currents is considerably milder than that of U-97775. In the α6β2γ2 subtype where these drugs have no agonistic activity, for instance, U-101017 at concentrations up to 80 μM, showed no appreciable effect on GABA currents, whereas U-97775 inhibited the currents with an IC50 value of 10 μM as measured 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 α1β2γ2 and α3β2γ2 subtypes. Furthermore, U-101017 was of higher efficacy in the α1β2γ2 than α3β2γ2 subtypes as compared to diazepam, although its binding affinity was not appreciably different in the two subtypes. We conclude that U-101017 is a partial benzodiazepine agonist, somewhat selective to the α1β2γ2 subtype, and with the ability to limit its own agonistic activity over a wide range of doses through its interaction with the low affinity site, but without potential convulsant activity, inherent to agents which block GABA currents.