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

In this paper we use NMR spectroscopy and molecular modeling to examine four vasopressin analogues substituted with bulky 3,3′-diphenylalanine (Dpa) enantiomers: [Mpa1,Dpa2,Val4,d-Arg8]VP (I), [Mpa1,d-Dpa2,Val4,d-Arg8]VP (II), [d-Dpa2,d-Arg8]VP (III) and [Mpa1,d-Dpa2]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 V1a receptor blocker.The conformational analysis has shown that β-turns at positions 2,3 and/or 3,4 are characteristic of OT antagonists. In turn, the β-turn in the Cys6-Gly9 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 Phe3 side chain is claimed to be important for V1a receptor affinity.

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