Wolfe J F, Rathman T L, Sleevi M C, Campbell J A, Greenwood T D
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061.
J Med Chem. 1990 Jan;33(1):161-6. doi: 10.1021/jm00163a027.
A series of 4(3H)-quinazolinones structurally related to 2-methyl-3-o-tolyl-4(3H)-quinazolinone (methaqualone, 3) were synthesized and evaluated for anticonvulsant activity. Preliminary screening of these compounds revealed that 2-[2-oxo-2-(4-pyridyl)ethyl]-3-aryl-4(3H)-quinazolinones 6l and 8i, 8k, and 8p-r having a single ortho substituent on the 3-aryl group had the most promising anticonvulsant activity. Compounds 6l and 8i possessing 3-o-tolyl and 3-o-chlorophenyl groups, respectively, showed good protection against MES- and scMet-induced seizures, combined with relatively low neurotoxicity after intraperitoneal administration in mice. They also exhibited low toxicity in tests for determining the mean hypnotic dose (HD50) and the median lethal dose (LD50). Although these compounds were markedly more potent as anticonvulsants when administered orally in mice and rats, they were also more neurotoxic. This neurotoxicity was particularly acute in oral tests with rats, which resulted in marginal protective indices. In drug differentiation tests, compound 6l was ineffective against seizures induced by bicuculline, picrotoxin, and strychnine, while 8i showed some protection against picrotoxin-induced seizures.
合成了一系列结构上与2-甲基-3-邻甲苯基-4(3H)-喹唑啉酮（甲喹酮，3）相关的4(3H)-喹唑啉酮，并对其抗惊厥活性进行了评估。对这些化合物的初步筛选表明，在3-芳基上具有单个邻位取代基的2-[2-氧代-2-(4-吡啶基)乙基]-3-芳基-4(3H)-喹唑啉酮6l和8i、8k以及8p-r具有最有前景的抗惊厥活性。分别具有3-邻甲苯基和3-邻氯苯基的化合物6l和8i，对最大电休克（MES）和皮下注射甲硫氨酸（scMet）诱导的癫痫发作具有良好的保护作用，并且在小鼠腹腔注射后神经毒性相对较低。在测定平均催眠剂量（HD50）和半数致死剂量（LD50）的试验中，它们也表现出低毒性。尽管这些化合物在小鼠和大鼠口服给药时作为抗惊厥药的效力明显更高，但它们的神经毒性也更大。这种神经毒性在大鼠口服试验中尤为严重，导致保护指数接近临界值。在药物鉴别试验中，化合物6l对荷包牡丹碱、印防己毒素和士的宁诱导的癫痫发作无效，而8i对印防己毒素诱导的癫痫发作有一定的保护作用。
