Synthesis, conformation analysis, and anxiolytic activity of retropeptide analogs of 4-cholecystokinin

Abstract

Potential dipeptide anxiolytics with the general formula Ph(CH2)5 CO-X-L-Trp-NH2(X = Gly, β-Ala, GABA, L-Pro) have been synthesized on the basis of the 4-cholecystokinin structure. These compounds exhibit anxiolytic activity in the elevated plus-maze test in rats at doses of 0.01–0.5 mg/kg (i.p.). The activity among these derivatives increases in the following order: GABA → β-Ala → Gly → Pro. Conformation analysis of dipeptides in solution by 1H NMR method with the use of the nuclear Overhauser effect and peptide vicinal 3J(H-NCα-H) coupling constants has been carried out. It is established that the percentage of βI-turn conformation stabilized by hydrogen bonds with the participation of C-end amide group proton also increases in the order β-Ala → Gly → Pro derivatives. It is concluded that the βI-turn conformation is probably the biologically active one in the synthesized substituted dipeptides.