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1U‐97775 (tert‐butyl 7‐chloro‐4,5‐dihydro‐5‐[(1‐(3,4,5‐trimethyl)piperazino)carbonyl]‐imidazo[1,5‐a])quinoxaline‐3‐carboxylate) is a novel GABAAreceptor ligand of dual functionality and was characterized for its interactions with cloned rat GABAAreceptors expressed in human embryonic kidney cells.2The drug produced a bell‐shaped dose‐response profile in the α1β2γ2 receptor subtype as monitored with GABA‐induced C1−currents in the whole cell patch‐clamp technique. At low concentrations (<0.5 μM), U‐97775 enhanced the currents with a maximal increase of 120% as normalized to 5 μMGABA response (control). An agonist interaction of U‐97775 with the benzodiazepine site is suggested, because Ro 15–1788 (an antagonist at the benzodiazepine site) abolished the current increase and [3H]‐flunitrazepam binding was inhibited by U‐97775 with a Kiof 1.2 nM.3The enhancement of GABA currents progressively disappeared as the U‐97775 concentration was raised above 1 μM, and the current amplitude was reduced to 40% below the control at 10 μMU‐97775. The current inhibition by U‐97775 (10 μM) was not affected by Ro 15–1788. It appears that U‐97775 interacts with a second site on GABA receptors, distinct from the benzodiazepine site, to reverse its agonistic activity on the benzodiazepine site and also to inhibit GABA currents.4U‐97775 at low concentrations reduced and at high concentrations enhanced [35S]‐TBPS binding. Ro 15–1788 selectively blocked the effect of U‐97775 at low concentrations. Analysis of the binding data in the presence of Ro 15–1788 yielded a single low affinity site with an estimated Kdof 407 nM.5In other αβγ receptor subtypes, U‐97775 at low concentrations enhanced C1−currents in the α3β2γ2 but not in the α6β2γ2 subtype. On the other hand, U‐97775 at high concentrations reduced C1−currents in all the receptor subtypes we examined, including those of two subunits, α1β2, β2γ2 and α1gamma;2 subtypes.6Therapeutically, U‐97775 could be unique among benzodiazepine ligands because of its ability to limit its own agonistic activity such that, at high doses the appearance of agonistic activity would be delayed until occupancy of its second site wanes. This property should make the total agonistic activity of U‐97775 relatively constant over a wide range of drug doses, and may minimize its liability to abuse. U‐97775 (tert‐butyl 7‐chloro‐4,5‐dihydro‐5‐[(1‐(3,4,5‐trimethyl)piperazino)carbonyl]‐imidazo[1,5‐a])quinoxaline‐3‐carboxylate) is a novel GABAAreceptor ligand of dual functionality and was characterized for its interactions with cloned rat GABAAreceptors expressed in human embryonic kidney cells. The drug produced a bell‐shaped dose‐response profile in the α1β2γ2 receptor subtype as monitored with GABA‐induced C1−currents in the whole cell patch‐clamp technique. At low concentrations (<0.5 μM), U‐97775 enhanced the currents with a maximal increase of 120% as normalized to 5 μMGABA response (control). An agonist interaction of U‐97775 with the benzodiazepine site is suggested, because Ro 15–1788 (an antagonist at the benzodiazepine site) abolished the current increase and [3H]‐flunitrazepam binding was inhibited by U‐97775 with a Kiof 1.2 nM. The enhancement of GABA currents progressively disappeared as the U‐97775 concentration was raised above 1 μM, and the current amplitude was reduced to 40% below the control at 10 μMU‐97775. The current inhibition by U‐97775 (10 μM) was not affected by Ro 15–1788. It appears that U‐97775 interacts with a second site on GABA receptors, distinct from the benzodiazepine site, to reverse its agonistic activity on the benzodiazepine site and also to inhibit GABA currents. U‐97775 at low concentrations reduced and at high concentrations enhanced [35S]‐TBPS binding. Ro 15–1788 selectively blocked the effect of U‐97775 at low concentrations. Analysis of the binding data in the presence of Ro 15–1788 yielded a single low affinity site with an estimated Kdof 407 nM. In other αβγ receptor subtypes, U‐97775 at low concentrations enhanced C1−currents in the α3β2γ2 but not in the α6β2γ2 subtype. On the other hand, U‐97775 at high concentrations reduced C1−currents in all the receptor subtypes we examined, including those of two subunits, α1β2, β2γ2 and α1gamma;2 subtypes. Therapeutically, U‐97775 could be unique among benzodiazepine ligands because of its ability to limit its own agonistic activity such that, at high doses the appearance of agonistic activity would be delayed until occupancy of its second site wanes. This property should make the total agonistic activity of U‐97775 relatively constant over a wide range of drug doses, and may minimize its liability to abuse.