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A study of the biologically active conformation of the cholecystokinin-4 dipeptide analogue GB-115

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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 analogues. 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 β-turn. Based on the data on the nuclear Overhauser effect 1H NMR spectroscopy, this structure was identified as the β-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-phenylhexanoyl)amino]-2-oxopyrrolidine-1-yl}-3-(1H-indole-3-yl)propionic acid ethyl ester, N-(6-phenylhexanoyl)glycyl-N α-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}carbonyl)amino]-3-(1H-indole-3-yl)propionic acid methyl ester confirmed that the β-turn of type II is the active conformation of GB-115.

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Abbreviations

EPM:

elevated plus-maze

IHB:

intramolecular hydrogen bond

NOE:

nuclear Overhauser effect; the configuration symbol in amino acids of the L series is omitted

MeTrp:

N α-methyltryptophan

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Authors and Affiliations

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

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

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  1. T. A. Gudasheva
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  2. V. P. Lezina
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  3. E. P. Kir’yanova
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  4. O. A. Deeva
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  5. L. G. Kolik
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  6. S. B. Seredenin
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Correspondence to T. A. Gudasheva.

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Original Russian Text © T.A. Gudasheva, V.P. Lezina, E.P. Kir’yanova, O.A. Deeva, L.G. Kolik, S.B. Seredenin, 2013, published in Bioorganicheskaya Khimiya, 2013, Vol. 39, No. 3, pp. 293–302.

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Gudasheva, T.A., Lezina, V.P., Kir’yanova, E.P. et al. A study of the biologically active conformation of the cholecystokinin-4 dipeptide analogue GB-115. Russ J Bioorg Chem 39, 259–267 (2013). https://doi.org/10.1134/S1068162013030060

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  • DOI: https://doi.org/10.1134/S1068162013030060

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