Influence of bulky 3,3'-diphenylalanine enantiomers replacing position 2 of AVP analogues on their conformations: NMR and molecular modeling studies

Eur J Med Chem. 2010 Sep;45(9):4065-73. doi: 10.1016/j.ejmech.2010.05.066. Epub 2010 Jun 8.

Abstract

In this paper we use NMR spectroscopy and molecular modeling to examine four vasopressin analogues substituted with bulky 3,3'-diphenylalanine (Dpa) enantiomers: [Mpa(1),Dpa(2),Val(4),D-Arg(8)]VP (I), [Mpa(1),D-Dpa(2),Val(4),D-Arg(8)]VP (II), [D-Dpa(2),D-Arg(8)]VP (III) and [Mpa(1),D-Dpa(2)]AVP (IV). All the peptides exhibit a strong and prolonged antidiuretic activity. Additionally, analogues II, III and IV display antiuterotonic activity and analogue II is also a weak V(1a) receptor blocker. The conformational analysis has shown that beta-turns at positions 2,3 and/or 3,4 are characteristic of OT antagonists. In turn, the beta-turn in the Cys(6)-Gly(9) fragment seems to be crucial for enhancement of the antidiuretic activity. The high accessibility of aromatic side chains at positions 2 and 3 plays a crucial role in antagonist-receptor binding. Moreover, orientation of the Phe(3) side chain is claimed to be important for V(1a) receptor affinity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Arginine Vasopressin / analogs & derivatives*
  • Arginine Vasopressin / chemistry
  • Magnetic Resonance Spectroscopy
  • Models, Molecular*
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemistry
  • Phenylalanine / metabolism
  • Protein Conformation
  • Stereoisomerism

Substances

  • Arginine Vasopressin
  • Phenylalanine
  • 3,3-diphenylalanine