Chemical Biology & Drug Design 2012-06-01

Highly potent antidiuretic antagonists: conformational studies of vasopressin analogues modified with 1-naphthylalanine enantiomers at position 2.

Emilia A Lubecka, Jerzy Ciarkowski, Adam Prahl, Emilia Sikorska

Index: Chem. Biol. Drug Des. 79(6) , 1033-42, (2012)

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Abstract

In this paper, we investigated the structure-activity relationship of two vasopressin analogues, [Cpa(1),(L-1-Nal)(2) ]AVP (I) and [Cpa(1),(D-Nal)(2) ]AVP (II) by NMR spectroscopy and molecular modeling. Both peptides exhibit antioxytocic and antipressor potency. Inversion of configuration of the residue at position 2 converted a weak antidiuretic agonist (peptide I) into a highly potent antidiuretic antagonist (peptide II). For this reason, the purpose of our study was to explain the causes of different interactions of the analogues with V(2) receptors. The results have shown that both analogues display the tendency to adopt β-turns in the 1-4 and 2-5 fragments, which is characteristic of OT and V(1a) receptors antagonists. In addition, the [Cpa(1),(L-1-Nal)(2) ]AVP (I) shows the propensity to assume β-turn at position 7,8, which is believed to enhance antidiuretic activity, although not being crucial for its appearance. Moreover, the C-terminal amide group seems to be crucial for signal transduction. Its high accessibility in [Cpa(1),(L-1-Nal)(2) ]AVP (I) in contrast to [Cpa(1),(D-1-Nal)(2) ]AVP (II), probably results in V(2) receptor activation.© 2012 John Wiley & Sons A/S.