Amnesia-reversal activity of a series of N-[(disubstituted-amino)alkyl]-2-oxo-1-pyrrolidineacetamides, including pramiracetam

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Abstract
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).