Antiseizure activity of novel gamma-aminobutyric acid (A) receptor subtype-selective benzodiazepine analogues in mice and rat models.
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.
Rivas
Felix M
FM
Department of Chemistry and Biochemistry, University of WisconsinsMilwaukee, Milwaukee, Wisconsin 53211, USA.
Stables
James P
JP
Murphree
Lauren
L
Edwankar
Rahul V
RV
Edwankar
Chitra R
CR
Huang
Shengming
S
Jain
Hiteshkumar D
HD
Zhou
Hao
H
Majumder
Samarpan
S
Sankar
Subramanian
S
Roth
Bryan L
BL
Ramerstorfer
Joachim
J
Furtmüller
Roman
R
Sieghart
Werner
W
Cook
James M
JM
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
D000927:Anticonvulsants; D003292:Convulsants; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D010433:Pentylenetetrazole