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

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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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

Keywords

  • cholecystokinin-4
  • dipeptide analogue
  • GB-115
  • 1H NMR spectroscopy
  • biologically active conformation
  • sterically restricted analogues
  • conformational analysis