2(3H)-苯并恶唑酮和2(3H)-苯并噻唑酮衍生物的合成及抗惊厥活性

Synthesis and anticonvulsant activity of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives.

作者信息

Ucar H, Van derpoorten K, Cacciaguerra S, Spampinato S, Stables J P, Depovere P, Isa M, Masereel B, Delarge J, Poupaert J H

机构信息

Laboratory of Medicinal Chemistry, School of Pharmacy, University of Louvain, Bruxelles, Belgium.

出版信息

J Med Chem. 1998 Mar 26;41(7):1138-45. doi: 10.1021/jm970682+.

DOI:10.1021/jm970682+

PMID:9544213

Abstract

A series of 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives were synthesized and evaluated for anticonvulsant activity. The compounds were assayed, intraperitoneally in mice and per os in rats, against seizures induced by maximal electroshock (MES) and pentylenetetrazole (scMet). Neurologic deficit was evaluated by the rotarod test. The compounds were prepared to determine the relationship between the 2(3H)-benzoxazolone and 2(3H)-benzothiazolone derivatives' structures and anticonvulsant activity. Several of these compounds showed significant anticonvulsant activity. Compounds 43 and 45 were the most active of the series against MES-induced seizures with ED50 values of 8.7 and 7.6 mg/kg, respectively. Compound 45 displayed good protection against MES-induced seizures and low toxicity in rats with an oral ED50 of 18.6 mg/kg and a protective index (PI = TD50/ED50) of < 26.9. In vitro receptor binding studies revealed that compounds 43 and 45 bind to sigma 1 receptors with nanomolar affinities.

摘要

合成了一系列2(3H)-苯并恶唑酮和2(3H)-苯并噻唑酮衍生物，并对其抗惊厥活性进行了评估。这些化合物通过腹腔注射给小鼠和口服给大鼠，用于测试其对最大电休克（MES）和戊四氮（scMet）诱导的癫痫发作的作用。通过转棒试验评估神经功能缺损。制备这些化合物是为了确定2(3H)-苯并恶唑酮和2(3H)-苯并噻唑酮衍生物的结构与抗惊厥活性之间的关系。其中几种化合物表现出显著的抗惊厥活性。化合物43和45是该系列中对MES诱导的癫痫发作最具活性的，其ED50值分别为8.7和7.6 mg/kg。化合物45对大鼠MES诱导的癫痫发作具有良好的保护作用且毒性较低，口服ED50为18.6 mg/kg，保护指数（PI = TD50/ED50）< 26.9。体外受体结合研究表明，化合物43和45以纳摩尔亲和力与σ1受体结合。