title: Piperazine imidazo[1,5-a]quinoxaline ureas as high-affinity GABAA ligands of dual functionality.
abstract: A series of imidazo[1,5-a]quinoxaline piperazine ureas appended with a tert-butyl ester side chain at the 3-position was developed. Analogues within this series have high affinity for the gamma-aminobutyric acid A (GABAA)/benzodiazepine receptor complex with efficacies ranging from inverse agonists to full agonists. Many analogues were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Uniquely, a number of these analogues were found to have a bell-shaped dose-response profile in the alpha1 beta2 gamma2 subtype as determined by whole cell patch-clamp technique, where in vitro efficacy was found to decrease with increasing drug concentration. Many of the compounds from this series were effective in antagonizing metrazole-induced seizures, consistent with anticonvulsant and possibly anxiolytic activity. Additionally, several analogues were also effective in lowering cGMP levels (to control values) after applied stress, also consistent with anxiolytic-like properties. The most effective compounds in these screens were also active in animal models of anxiety such as the Vogel and Geller assays. The use of the piperazine substituent allowed for excellent drug levels and a long duration of action in the central nervous system for many of the quinoxalines, as determined by ex vivo assay. Pharmacokinetic analysis of several compounds indicated excellent oral bioavailability and a reasonable half-life in rats. From this series emerged two partial agonists (55, 91) which had good activity in anxiolytic models, acceptable pharmacokinetics, and minimal benzodiazepine-type side effects.
authors: Departments of Structural, Analytical and Medicinal Chemistry, Central Nervous System Diseases Research, Computer Aided Drug Discovery, and Pharmacokinetics and Bioanalysis Research, Upjohn Laboratories, Kalamazoo, Michigan 49001, USA.
authors: E J
authors: EJ
authors: Jacobsen
authors: L S
authors: LS
authors: Stelzer
authors: R E
authors: RE
authors: TenBrink
authors: K L
authors: KL
authors: Belonga
authors: D B
authors: DB
authors: Carter
authors: H K
authors: HK
authors: Im
authors: W B
authors: WB
authors: Im
authors: V H
authors: VH
authors: Sethy
authors: A H
authors: AH
authors: Tang
authors: P F
authors: PF
authors: VonVoigtlander
authors: J D
authors: JD
authors: Petke
authors: W Z
authors: WZ
authors: Zhong
authors: J W
authors: JW
authors: Mickelson
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000927:Anticonvulsants / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001007:Anxiety / Q000378:metabolism / Q000503:physiopathology; D001682:Biological Availability; D002460:Cell Line; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000633:toxicity; D006152:Cyclic GMP / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D018755:GABA Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D010433:Pentylenetetrazole / Q000633:toxicity; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C118868:7-chloro-5-((1-(3,5-dimethyl)piperazino)carbonyl)-4,5-dihydroimidazo(1,5-a)quinoxaline-3-carboxylic acid 1,1-dimethylethyl ester; C118869:7-trifluoromethyl-4,4-dimethyl-4,5-dihydro-5-((1-(3,5-dimethyl)piperazino)carbonyl)imidazo(1,5-a)quinoxaline-3-carboxylic acid 1,1-dimethylethyl ester; D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D003292:Convulsants; D018755:GABA Agonists; D007093:Imidazoles; D008024:Ligands; D010879:Piperazines; D011810:Quinoxalines; D011963:Receptors, GABA-A; D014508:Urea; D006152:Cyclic GMP; D010433:Pentylenetetrazole