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We describe the synthesis, pharmacological properties, and structures of antidiuretic agonists, arginine vasopressin (AVP) and [ d-Arg]-vasopressin (DAVP), and their inverso analogues. The structures of the peptides are studied based on micellar and liposomic models of cell membranes using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic-zwitterionic micelles are obtained using NMR spectroscopy and molecular dynamics simulations. NMR data have shown that AVP and DAVP tend to adopt typical of vasopressin-like peptides β-turns: in the 2-5 and 3-6 fragments. The inverso-analogues also adopt β-turns in the 3-6 fragments. For this reason, their inactivity seems to be due to the difference in side chains orientations of Tyr, Phe, and Arg, important for interactions with the receptors. Again, the potent antidiuretic activity of DAVP can be explained by CD data suggesting differences in mutual arrangement of the aromatic side chains of Tyr and Phe in this peptide in liposomes rather than of native AVP. In the presence of liposomes, the smallest conformational changes of the peptides are noticed with DPPC and the largest with DPPG liposomes. This suggests that electrostatic interactions are crucial for the peptide-membrane interactions. We obtained similar, probably active, conformations of the antidiuretic agonists in the mixed DPC/SDS micelles (5:1) and in the mixed DPPC/DPPG (7:3) liposomes. Thus it can be speculated that the anionic-zwitterionic liposomes as well as the anionic-zwitterionic micelles, mimicking the eukaryotic cell membrane environment, partially restrict conformational freedom of the peptides and probably induce conformations resembling those of biologically relevant ones. [ABSTRACT FROM AUTHOR]

Two glycosylated peptides have been studied using NMR spectroscopy supported by molecular modeling. Peptide I is an oxytocin (OT) analogue in which glutamine 4 was replaced by serine with attached α- d-mannose through the oxygen β atom, whereas peptide II is a lysine-vasopressin (LVP) analogue with lysine 8 side chain modified by the attachment of glucuronic acid through an amide bond. Both peptides exhibit very weak uterotonic effect and are less susceptible to proteolytic degradation than the mother hormones. Additionally, peptide II reveals very weak pressor and antidiuretic activities. Our results have shown that the conformational preferences of glycosylated analogues are highly similar to those of their respective mother hormones. OT glycosylated analogue (I) exhibits a 3,4 β-turn characteristic of OT-like peptides, and vasopressin-glycosylated analogue (II) exhibits β-turns typical of vasopressin-like peptides. Therefore, the lack of binding of the glycosylated analogues to the receptors can be attributed to a steric interference between the carbohydrate moieties and the receptors. We also consider this to be the reason of the very low activity of the analyzed glycopeptides. We expect that results from these studies will be helpful in designing new OT-like and vasopressin-like drugs. Copyright © 2014 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this paper, we investigated the structure-activity relationship of two vasopressin analogues, [Cpa1,(L-1-Nal)2]AVP ( I) and [Cpa1,(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 V2 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 V1a receptors antagonists. In addition, the [Cpa1,(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 [Cpa1,(L-1-Nal)2]AVP ( I) in contrast to [Cpa1,(D-1-Nal)2]AVP ( II), probably results in V2 receptor activation. [ABSTRACT FROM AUTHOR]

Abstract: In this paper, we use NMR spectroscopy and molecular modeling to examine four new vasopressin analogs modified with α-2-indanylglycine (Igl) at position 2, [L-Igl2]AVP (I), [D-Igl2]AVP (II), [Mpa1,L-Igl2]AVP (III) and [Mpa1,D-Igl2]AVP (IV), embedded in a sodium dodecyl sulfate (SDS) micelle. All the analogs display antiuterotonic activity. In addition, the analogs with D-Igl reveal antipressor properties. Each analog exhibits the tendency to adopt β-turns at positions 2, 3 and/or 3, 4, which is characteristic of oxytocin-like peptides. Mutual arrangement of aromatic residues at positions 2 and 3 has been found to be crucial for binding antagonists with the OT and V1a receptors. The orientation of the Gln4 side chain seems to be important for the V1a receptor affinity. In each of the peptides studied, the Gln4 side chain is folded back over the ring moiety. However, it lies on the opposite face of the tocin moiety in analogs with L and D enantiomers of Igl. [ABSTRACT FROM AUTHOR]