AMNESIA-REVERSAL ACTIVITY OF A SERIES OF N-[(DISUBSTITUTED-AMINO)ALKYL]-2-OXO-1-PYRROLIDINEACETAMIDES, INCLUDING PRAMIRACETAM
AMNESIA-REVERSAL ACTIVITY OF A SERIES OF N-[(DISUBSTITUTED-AMINO)ALKYL]-2-OXO-1-PYRROLIDINEACETAMIDES, INCLUDING PRAMIRACETAM
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DOI：
10.1021/jm00371a023
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发表时间：
1984-01-01
影响因子：
7.3
通讯作者：
MARRIOTT, JG
中科院分区：
文献类型：
--
作者：
BUTLER, DE;NORDIN, IC;MARRIOTT, JG
合成了一系列N-[（二烷氨基）烷基]-2-氧代-1-吡咯烷乙酰胺类化合物。标题化合物逆转电惊厥休克（ECS）治疗后给药时诱导的小鼠健忘症，并在CNS活性的一般观察试验中无活性。活性化合物呈现倒U形剂量-反应曲线。在具有最宽剂量-反应曲线以及最有效的化合物中，是具有N-[2-[双（1-甲基）氨基]乙基]或2，6-二甲基哌啶基乙基残基作为酰胺取代基的化合物。的N-（二烷基氨基）取代基显着增强健忘症逆转活性，乙烯提供最佳的链长。选择N-[2-[双（1-甲基乙基）氨基]乙基]-2-氧代-1-吡咯烷乙酰胺N-（二烷基氨基）取代基进行临床前毒理学评价，指定研究编号CI-879和美国采用名称（USAN）普拉西坦。普拉西坦在动物中表现出较宽的安全范围，在正常人类志愿者中耐受良好。它在原发性退行性痴呆（PDD或阿尔茨海默型老年痴呆）患者的开放标签试验中显示出令人鼓舞的活性。
A series of N-[(dialkylamino)alkyl]-2-oxo-1-pyrrolidineacetamides was synthesized. The title compounds reversed electroconvulsive shock (ECS) induced amnesia in mice when administered subsequent to the ECS treatment and were inactive in a general observational test for CNS activity. Active compounds exhibited an inverted U-shaped dose-response curve. Among the compounds with the broadest dose-response curve, as well as the most potent, were those with the N-[2-[bis(1-methyl)amino]ethyl] or 2,6-dimethylpiperidinoethyl residues as amide substituent. The N-(dialkylamino) substituent markedly enhances amnesia-reversal activity, with ethylene providing the optimal chain length. N-[2-[Bis(1-methylethyl)amino]ethyl]-2-oxo-1-pyrrolidineacetamide N-(dialkylamino) substituent was selected for preclinical toxicological evaluation, assigned the investigational number CI-879 and U.S. adopted name (USAN) pramiracetam. Pramiracetam demonstrated a wide margin of safety in animals and was well tolerated in normal human volunteers. It showed encouraging activity in an open label trial in patients with primary degenerative dementia (PDD or senile dementia of the Alzheimer''s type).