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

• Published in: Journal of medicinal chemistry Vol. 27; no. 5; pp. 684 - 691
• Main Authors: Butler, Donald E, Nordin, Ivan C, L'Italien, Yvon J, Zweisler, Lynette, Poschel, Paul H, Marriott, John G
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.05.1984
• Subjects: Amnesia - drug therapy; Animals; Biological and medical sciences; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Electroshock; General pharmacology; Humans; Male; Medical sciences; Mice; Mice, Inbred Strains; Pharmacology. Drug treatments; Physicochemical properties. Structure-activity relationships; Pyrrolidines - chemical synthesis; Pyrrolidines - therapeutic use; Structure-Activity Relationship; Carboxamide; Five membered ring; Amnesia; Structure activity relation; Nitrogen heterocycle; Lactam
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00371a023

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 central nervous system (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-methylethyl)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 the U.S. adopted name ( USAN ) pramiracetam . Pramiracetam demonstrated a wide margin of safety in animals and was well tolerated in normal human volunteers. It has shown encouraging activity in an open label trial in patients with primary degenerative dementia (PDD or senile dementia of the Alzheimer's type).