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

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• 作者：O. A. Gudasheva ; V. P. Lezina ; E. P. Kir¡¯yanova ; V. S. Troitskaya ; L. G. Kolik and S. B. Seredenin
• 刊名：Pharmaceutical Chemistry Journal
• 出版年：2006
• 出版时间：July, 2006
• 年：2006
• 卷：40
• 期：7
• 页码：367-372
• 全文大小：121 KB

文摘

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.