title: Synthesis and anticonvulsant activity of 1,3-dihydro-5-phenyl-2H-pyrido[3,2-e]-1,4-diazepin-2-ones.
abstract: 1,3-Dihydro-5-phenyl-2H-pyrido[3,2-e]-1,4-diazepin-2-ones (11-13), in which the chlorophenyl ring of 7-chloro-1,4-benzodiazepin-2-ones is replaced by a pyridyl ring, were synthesized and evaluated as anticonvulsants using subcutaneous pentylenetetrazole (scPTZ) and maximal electroshock (MES) induced seizure screening tests. A methyl substituent at the N-1 and/or C-3 position of the diazepin-2-one ring system was not a determinant of scPTZ activity, but the 1,3-dimethyl derivative (13) was more potent than the parent 1,3-unsubstituted compound (11) in the MES screen. 1,3-Dihydro-1,3-dimethyl-5-phenyl-2H-pyrido[3,2-e]-1,4-diazepin-2- one (13) inhibited sc bicuculline and sc picrotoxin induced seizures, but it did not inhibit in vitro benzodiazepine binding which suggests it may act by a different mechanism of action. In the mouse Phase II scPTZ screen all compounds tested were less active than clonazepam but more active than valproic acid.
authors.affiliation: Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.
authors.forename: C Y
authors.initials: CY
authors.lastname: Fiakpui
authors.forename: E E
authors.initials: EE
authors.lastname: Knaus
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001640:Bicuculline / Q000009:adverse effects / Q000037:antagonists & inhibitors; D004353:Drug Evaluation, Preclinical; D051379:Mice; D010433:Pentylenetetrazole / Q000009:adverse effects / Q000037:antagonists & inhibitors; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D011728:Pyridones; D010433:Pentylenetetrazole; D001640:Bicuculline