title: Antiseizure activity of novel gamma-aminobutyric acid (A) receptor subtype-selective benzodiazepine analogues in mice and rat models.
abstract: The antiseizure activity of benzodiazepines (BDZs) 1-5 in mice and rats as animal models is described. These BDZs have selective efficacy for alpha2beta3gamma2 and alpha3beta3gamma2 GABA(A)-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8-44 (mice, ip) were observed for compounds 2-4 in the subcutaneous metrazole seizure (scMET) test. In rats, orally (po) the TI was >5 to 105. These compounds represent novel leads in the search for anticonvulsants devoid of sedative, ataxic, and amnestic side effects.
authors.affiliation: Department of Chemistry and Biochemistry, University of WisconsinsMilwaukee, Milwaukee, Wisconsin 53211, USA.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Rivas
authors.forename: James P
authors.initials: JP
authors.lastname: Stables
authors.forename: Lauren
authors.initials: L
authors.lastname: Murphree
authors.forename: Rahul V
authors.initials: RV
authors.lastname: Edwankar
authors.forename: Chitra R
authors.initials: CR
authors.lastname: Edwankar
authors.forename: Shengming
authors.initials: S
authors.lastname: Huang
authors.forename: Hiteshkumar D
authors.initials: HD
authors.lastname: Jain
authors.forename: Hao
authors.initials: H
authors.lastname: Zhou
authors.forename: Samarpan
authors.initials: S
authors.lastname: Majumder
authors.forename: Subramanian
authors.initials: S
authors.lastname: Sankar
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Joachim
authors.initials: J
authors.lastname: Ramerstorfer
authors.forename: Roman
authors.initials: R
authors.lastname: Furtmüller
authors.forename: Werner
authors.initials: W
authors.lastname: Sieghart
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D001569:Benzodiazepines / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D003292:Convulsants; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects; D008024:Ligands; D051379:Mice; D010433:Pentylenetetrazole; D051381:Rats; D011963:Receptors, GABA-A / Q000378:metabolism*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy; D013329:Structure-Activity Relationship
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D010433:Pentylenetetrazole