Antiseizure Activity of Novel γ-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 α2β3γ2 and α3β3γ2 GABAA-receptors. Significant anticonvulsant activity with little or no motor impairment and therapeutic indexes (TI) of 2.8−44 (mice, ip) we...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-04, Vol.52 (7), p.1795-1798
Hauptverfasser:	Rivas, Felix M, Stables, James P, Murphree, Lauren, Edwankar, Rahul V, Edwankar, Chitra R, Huang, Shengming, Jain, Hiteshkumar D, Zhou, Hao, Majumder, Samarpan, Sankar, Subramanian, Roth, Bryan L, Ramerstorfer, Joachim, Furtmüller, Roman, Sieghart, Werner, Cook, James M
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Anticonvulsants - chemical synthesis Anticonvulsants - pharmacology Anticonvulsants - toxicity Anticonvulsants. Antiepileptics. Antiparkinson agents Benzodiazepines - chemical synthesis Benzodiazepines - pharmacology Benzodiazepines - toxicity Biological and medical sciences Convulsants Hippocampus - drug effects Hippocampus - physiopathology Kindling, Neurologic - drug effects Ligands Medical sciences Mice Neuropharmacology Pentylenetetrazole Pharmacology. Drug treatments Rats Receptors, GABA-A - metabolism Seizures - chemically induced Seizures - drug therapy Structure-Activity Relationship
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Zusammenfassung:	The antiseizure activity of benzodiazepines (BDZs) 1−5 in mice and rats as animal models is described. These BDZs have selective efficacy for α2β3γ2 and α3β3γ2 GABAA-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.
ISSN:	0022-2623 1520-4804 1520-4804
DOI:	10.1021/jm801652d