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

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 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).

Hormesis: Why it is important to toxicology and toxicologists

“…This has been exploited in the pharmaceutical industry in search of biphasic dose responses that may lead to new drugs to reduce anxiety [50–52]. Many examples exist of agents that will differentially induce a U‐shaped dose response to optimize a memory response using structure‐activity relationship methods [53,54]. It therefore is necessary to place the above statement of Stebbing–namely, that all chemicals can induce hormesis–within a broader context.…”

Ugi Four-Center Three-Component Reaction as a Direct Approach to Racetams

“…The product was purified by column chromatography on silica gel (EtOAc to EtOAc/MeOH, 19:1). N-[2-(Diisopropylamino)ethyl]-2-(2-oxopyrrolidin-1-yl)acetamide (4ee) 31 To Ugi product 4o (20 mg, 0.065 mmol, 1 equiv) was added N1,N1diisopropylethane-1,2-diamine (0.1 mL) and the mixture was stirred at 110 °C for 11 h (under N 2 atmosphere). Crude NMR analysis indicated the complete conversion of 4o into 4ee and 2-amino-6-bromopyridine.…”

Towards Better Brain Management: Nootropics

“…It ameliorates drug-induced amnesia resulting from dysfunction in the cholinergic neuronal system [122]. It stimulates acetylcholine release by acting on the GABAergic neuronal system in frontal cortex of rats and potentiates cholinergic neuronal function to modify acquisition and/or Pramiracetam (4) has been found to be one of the most active agents in reversing amnesia in mice and which exhibited a wide active dose range and a wide margin of safety [112]. It exhibits good efficacy in both animal models of memory or learning impairment and patients with senile and presenile cognitive impairment, including dementia of Alzheimer's type [113].…”