title: 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 GABA(A) 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 alpha 6 beta 2 gamma 2 subtype where these drugs have no agonistic activity, for instance, U-101017 at concentrations up to 80 mu M, showed no appreciable effect on GABA currents, whereas U-97775 inhibited the currents with an IC(50) value of 10 mu M 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 alpha 1 beta 2 gamma 2 and alpha 3 beta 2 gamma 2 subtypes. Furthermore, U-101017 was of higher 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 not 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 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.
authors.affiliation: CNS Diseases Research, The Upjohn Company, Kalmazoo, MI 49001, USA.
authors.forename: H K
authors.initials: HK
authors.lastname: Im
authors.forename: W B
authors.initials: WB
authors.lastname: Im
authors.forename: P F
authors.initials: PF
authors.lastname: Von Voigtlander
authors.forename: D B
authors.initials: DB
authors.lastname: Carter
authors.forename: B H
authors.initials: BH
authors.lastname: Murray
authors.forename: E J
authors.initials: EJ
authors.lastname: Jacobsen
mesh_terms: D000818:Animals; D002460:Cell Line / Q000187:drug effects; D018118:Chloride Channels / Q000187:drug effects*; D003975:Diazepam / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007668:Kidney / Q000187:drug effects; D011804:Quinolines / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects*
chemical_list: C104547:7-chloro-5((cis-3,5-dimethylpiperazine)carbonyl)imidazo(1,5a)quinoline-3-carboxylate; D018118:Chloride Channels; D011804:Quinolines; D011963:Receptors, GABA-A; D003975:Diazepam