Letters in Drug Design Discovery.pdf

Letters in Drug Design Discovery, 2009, 6, ???-??? 1 1570-1808/09 $55.00+.00 ? 2009 Bentham Science Publishers Ltd. Synthesis, Anticonvulsant Evaluation of 2,3,4,5-Tetrahydro-7-alkoxy-1H- 2-benzazepin-1-ones Cheng-Xi Wei, Wei Zhang, Zhe-Shan Quan, Rong-Bi Han, Ri-Shan Jiang and Feng-Yu Piao* Key Laboratory of Natural Resources and Functional Molecules of the Changbai Mountain, Affiliated Ministry of Education, Yanbian University College of Pharmacy, Yanji 133000, Jilin Province, P.R. China Received May 17, 2009: Revised June 25, 2009: Accepted June 26, 2009 Abstract: A series of novel 2,3,4,5-tetrahydro-7-alkoxy-1H-2-benzazepin-1-ones derivatives was synthesized and screened for its anticonvulsant activities by the maximal electroshock (MES) test and its neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox). The MES is the most commonly used method of screening antiepileptic drugs. 2,3,4,5-tetrahydro-7-heptyloxy-1H-2-benzazepin-1-one 4e, revealed as the best anticonvulsant activity, exhibited median effective dose (ED50) of 39.4 mg/kg, and median toxicity dose (TD50) of 392.9 mg/kg, resulting in a protective index (PI) of 10.0, which is a little higher than the PI of the marked antiepileptic drug carbamazepine (PI=6.4). Comound 4e also un- derwent further anticonvulsant tests evaluating its activity in some chemically induced seizure models, including pentyle- netetrazole (PTZ), isoniazid, 3-mercaptopropionic acid (3-MP), and thiosemicarbazide. Keywords: Anticonvulsant, Benzo[c]azepinone, Synthesis. 1. INTRODUCTION In our previous study [1], a series of derivatives of 6- alkoxy-3,4-dihydro-2(1H)-quinoline was first found to have anticonvulsant activities, among which 6-hexyloxy-3,4- dihydro-2(1H)-quinolinone (compound I) showed the strongest activity with an ED50 value of 24.0 mg/kg in the maximal electroshock test (MES) and TD50 value of 56.3 mg/kg. In our attempts to obtain compounds with better anti- convulsant activity and