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

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)...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 1984-05, Vol.27 (5), p.684-691
Main Authors: Butler, Donald E, Nordin, Ivan C, L'Italien, Yvon J, Zweisler, Lynette, Poschel, Paul H, Marriott, John G
Format: Article
Language:English
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
Citations: Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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).
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00371a023