Antiseizure activity of novel gamma-aminobutyric acid (A) receptor subtype-selective benzodiazepine analogues in mice and rat models

  • J Med Chem. 2009 Apr 9;52(7):1795-8. doi: 10.1021/jm801652d.
Felix M Rivas  1 ,  James P Stables ,  Lauren Murphree ,  Rahul V Edwankar ,  Chitra R Edwankar ,  Shengming Huang ,  Hiteshkumar D Jain ,  Hao Zhou ,  Samarpan Majumder ,  Subramanian Sankar ,  Bryan L Roth ,  Joachim Ramerstorfer ,  Roman Furtmüller ,  Werner Sieghart ,  James M Cook
Affiliations
  • 1. Department of Chemistry and Biochemistry, University of WisconsinsMilwaukee, Milwaukee, Wisconsin 53211, USA.
PMID: 19275170 DOI: 10.1021/jm801652d
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.

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