2-Phenyl-3H-imidazo[4,5-b]pyridine-3-acetamides as non-benzodiazepine anticonvulsants and anxiolytics.
A series of 2-phenyl-3H-imidazo[4,5-b]pyridine-3-acetamides were designed and synthesized as non-benzodiazepine anxiolytics based on a molecular disconnection of a typical 1,4-benzodiazepine (BZD). A number of these compounds showed submicromolar potency in a [3H]benzodiazepine binding assay in vitro and good potency in protecting rodents against pentylenetetrazole-induced seizures. Compound 84 appears to be a selective anticonvulsant (pentylenetetrazole) agent when tested against a profile of chemically and electrically induced seizures in mice. In addition, compound 148 appears to be a selective anxiolytic/hypnotic agent on the basis of biochemical and pharmacological characterization. It appears to be a full BZD agonist as assessed by GABA shift ratio and to be effective in punishment and nonpunishment animal models of anxiety. In addition, it shows a lower side-effect profile than diazepam as assessed by rotorod neurotoxicity and potentiation of ethanol-induced sleep time in mice. The chemistry and structure-activity relationships of this series is discussed.
Department of Chemical Research, A. H. Robins Company, Richmond, Virginia 23261-6609.
B E
BE
Tomczuk
C R
CR
Taylor
L M
LM
Moses
D B
DB
Sutherland
Y S
YS
Lo
D N
DN
Johnson
W B
WB
Kinnier
B F
BF
Kilpatrick
D000818:Animals; D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000627:therapeutic use; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy; D001569:Benzodiazepines / Q000378:metabolism; D001667:Binding, Competitive; D002540:Cerebral Cortex / Q000378:metabolism; D007093:Imidazoles / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D051379:Mice; D008813:Mice, Inbred ICR; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D014151:Anti-Anxiety Agents; D000927:Anticonvulsants; D007093:Imidazoles; D011725:Pyridines; D011963:Receptors, GABA-A; C069610:2-(4-chlorophenyl)-3H-imidazo(4,5-b)pyridine-3-acetamide; C071270:5-chloro-N,N-dimethyl-2-(4-methylphenyl)-3H-imidazo(4,5-b)pyridine-3-acetamide; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid