103322-29-8

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A novel approach to the search for the new groups of biologically active peptides is developed, which is based on the selection of point mutants with respect to noncritical amino acid residues. Using a gene site encoding the arginine vasopressin AVP(4-5) sequence, which corresponds to the pGlu-Asn-NH2 nootropic dipeptide, three point mutants with respect to Asn (pGlu-Ser-NH2, pGlu-Asp-NH2, and pGlu-His-NH 2) have been synthesized. The first two peptides (corresponding to transitions of the 1st and 2nd bases, respectively) display nootropic activity in the passive avoidance test in rats at a dose of 0.1 mg/kg (i.p.). The last peptide (corresponding to a transversion of the 1st base) proved to be inactive. Both active peptides exhibit electronic and structural differences from the parent dipeptide: pGlu-Asp-NH2 bears a negative charge and contains a primary alcohol group instead of the amide moiety. Using the proposed method, it is possible to create genetically related analogs of well-known neuropeptides with substantially different structures.

Four diastereomers of pGlu-Asn-NH2 were synthesized.They were considered on one hand as a peptide analogue of piracetam, and on the other as an N-terminal fragment of the major metabolite of vasopressin 4, Cyt6>AVP(4-9).The influence of these diastereomers on the memory of rats was studied in the passive avoidance conditioned reflex test.It was shown that L-pGlu-L-Asn-NH2 and D-pGlu-D-Asn-NH2 in the same doses facilitate the training of rats; D-pGlu-D-Asn-NH2 is inactive, and L-pGlu-D-Asn-NH2 has amnestic activity.These facts suggest a receptor mechanism for the action of the dipeptide pGlu-Asn-NH2 and are the basis for a hypothesis for the topology of the nootropic receptor binding site.