Synthesis and antiamnesic activity of a series of N-acylprolyl-containing dipeptides

Esters and amides of a series of N-acylprolyl-containing dipeptides were synthesized. It was established that these substances possess the ability to prevent memory decline evoked by maximal electroshock (MES) in a passive avoidance step-through paradigm. These N-acylprolyl-containing dipeptides were designed as analogues of pyroglutamyl-containing dipeptides, which we previously demonstrated to be highly active nootropics. Among the structure-activity relationships explored were the effect of N-acyl-substitution size, C-terminal substitution and the nature of the second amino acid. The optimal N-acyl moiety was the N-phenyl-acetyl group, while the optimal C-terminal substitution-esters were those derived from low alkyl alcohols. The optimal second amino acids were Asp, Glu or their fragments, Gly, beta-Ala, GABA. Compound 1 (N-phenylacetylprolylglycine ethyl ester) was selected for further evaluation in impaired cognitive functions. It was supposed that esters and unsubstituted amides of N-acylprolylglycines are prodrugs,which convert to the bioactive cyclo-(Pro-Gly) by virtue of enzymatic or chemical lability within the body.