A Study of the Biologically Active Conformation of the
Cholecystokinin-4 Dipeptide Analogue GB-115

T. A. Gudasheva¹, V. P. Lezina, E. P. Kir’yanova, O. A. Deeva, L. G. Kolik, and S. B. Seredenin

Zakusov Research Institute of Pharmacology, Russian Academy of Medical Sciences,
ul. Baltiiskaya 8, Moscow, 125315 Russia

Received June 29, 2012; in final form, October 30, 2012

Abstract—The biologically active conformation of N-(6-phenylhexanoyl)glycyl-tryptophan amide (GB-115),
a highly active cholecystokinin-4 retro dipeptide analogue with the anxiolytic activity, has been studied using
the conformational analysis by ¹H NMR spectroscopy in solution and the method of sterically restricted ana-
logues. A study of the relationship between the preferable conformation in solution and the anxiolytic activity
in the series of GB-115 derivatives showed that the biologically active conformation of this compound is the -
turn. Based on the data on the nuclear Overhauser effect ¹H NMR spectroscopy, this structure was identified as
the -turn of type II. Subsequent synthesis and study of the pharmacological activity of novel sterically
restricted analogues of dipeptide GB-115: (2S)-2-{(3R)-3-[(6-phenylhexa-noyl)amino]-2-oxopyrrolidine-1-
yl}-3-(1H-indole-3-yl)propionic acid ethyl ester, N-(6-phenylhexa-noyl)glycyl-N-methyltryptophan ethyl
ester, (2S)-2-[(10,11-dihydro-5H-dibenzo[b, f]azepin-5-ylcarbonyl)amino]-3-(1H-indole-3-yl)propionic acid
methyl ester, and (2S)-2-[({3-[(ethoxycarbonyl)amino]-10,11-dihydro-5H-dibenzo[b, f]azepin-5-yl}carbo-
nyl)amino]-3-(1H-indole-3-yl)propionic acid methyl ester confirmed that the -turn of type II is the active con-
formation of GB-115.

Keywords: cholecystokinin-4, dipeptide analogue, GB-115, ¹H NMR spectroscopy, biologically active confor-
mation, sterically restricted analogues, conformational analysis

DOI: 10.1134/S1068162013030060

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