High-affinity partial agonist imidazo[1,5-a]quinoxaline amides, carbamates, and ureas at the gamma-aminobutyric acid A/benzodiazepine receptor complex.
A series of imidazo[1,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the gamma-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying efficacies ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [35S]TBPS and Cl- current ratios. Many of these compounds were also effective in antagonizing metrazole-induced seizures in accordance with anticonvulsant and possible anxiolytic activity. Selected quinoxalines displayed limited benzodiazepine-type side effects such as ethanol potentiation and physical dependence in animal models. Dimethylamino urea 41 emerged as the most interesting analog, having a partial agonist profile in vitro while possessing useful activity in animal models of anxiety such as the Vogel and Geller assays. In accordance with its partial agonist profile, 41 was devoid of typical benzodiazepine side effects.
Jacobsen
E J
EJ
Department of Medicinal Chemistry, Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001, USA.
TenBrink
R E
RE
Stelzer
L S
LS
Belonga
K L
KL
Carter
D B
DB
Im
H K
HK
Im
W B
WB
Sethy
V H
VH
Tang
A H
AH
VonVoigtlander
P F
PF
Petke
J D
JD
D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D001569:Benzodiazepines / Q000494:pharmacology; D001667:Binding, Competitive; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D005445:Flunitrazepam / Q000037:antagonists & inhibitors / Q000378:metabolism; D018755:GABA Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D018756:GABA Antagonists / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D010069:Oxadiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010433:Pentylenetetrazole / Q000494:pharmacology; D011810:Quinoxalines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*
C097773:3--(5-cyclopropyl-1,2,4-oxadiazol-3-yl)-5-((dimethylamino)carbonyl)-4,5-dihydroimidazo(1,5-a)quinoxaline; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002712:Chlorides; D018755:GABA Agonists; D018756:GABA Antagonists; D010069:Oxadiazoles; D011810:Quinoxalines; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005445:Flunitrazepam; C037476:tert-butylbicyclophosphorothionate; D010433:Pentylenetetrazole