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ABSTRACT Deamination of vasopressin (AVP) enhances its antidiuretic activity. Moreover, introduction of D-Arg8 instead of its L enantiomer in deamino-vasopressin (dAVP) results in an extremely potent and selective antidiuretic agonist - desmopressin (dDAVP). In this study we describe the synthesis, pharmacological properties and structures of these two potent antidiuretic agonists, and their inverso analogs. The structures of the peptides are studied in micellar and liposomic models of cell membrane using CD spectroscopy. Additionally, three-dimensional structures in mixed anionic-zwitterionic micelles are obtained using NMR spectroscopy supported by molecular dynamics simulations. Our conformational studies have shown that desmopressin in a membrane mimicking environment adopts one of the characteristic for vasopressin-like peptides β-turn - in position 3,4. Furthermore, dDAVP shows the tendency to create a β-turn in the Cys6-Gly9 C-tail, considered to be important for the antidiuretic activity, and also some tendency to adopt a 5,6 β-turn. In desmopressin, in contrast to the native vasopressin, deamino-vasopressin and [D-Arg8]-vasopressin (DAVP), the Arg8 side chain, crucial for the pressor and antidiuretic activities, is very well exposed for interaction with the receptor, whereas Gly9, crucial for the pressor and uterotonic activities, is situated together with the C-terminal amide group very close to the tocin ring. The arrangements of the Gln4 and Asn5 side chains, being crucial for OT activity, also differ in desmopressin as compared to those of AVP, dAVP and DAVP. These differences in arrangement of the important for activities side chains are likely to explain extremely potent and selective antidiuretic activities of desmopressin. © 2016 Wiley Periodicals, Inc. Biopolymers (Pept Sci) 106: 245-259, 2016. [ABSTRACT FROM AUTHOR]

Raman (RS), surface-enhanced Raman scattering (SERS), electrochemistry, and isotopic effect methods were used to characterize selective adsorption of two isotopically labeled bradykinin analogues, [(Phe-D5)5]BK and [(Phe-D5)8]BK, a hormone which is known to be involved in small-cell and non-small-cell lung carcinoma and prostate cancer. The investigated analogues contain Phe residue, at position 5 or 8 in the amino acid sequence, substituted by Phe-D5 (five protons of L-phenylalanine ring substituted by deuterium). [(Phe-D5)5]BK and [(Phe-D5)8]BK were immobilized onto electrochemically roughened Ag, Au, and Cu electrode surfaces under different applied electrode potentials (−1.000 V to 0.200 V) in an aqueous solution containing 0.01 M phosphate buffer (pH = 7.0) and 0.1 M Na2SO4. Based on the analyses of the spectral profiles in the 920 - 1050 cm−1 spectral range, specific conclusions were drawn with respect to the Phe⋅⋅⋅metal interactions and changes in the interaction that occurred when the adsorption conditions were varied. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this paper, the surface-enhanced Raman scattering (SERS) spectra of the potent B2 bradykinin receptor antagonists, [D-Arg0,Hyp3,Thi5,8,L-Pip7]BK, Aaa[D-Arg0,Hyp3,Thi5,8,L-Pip7]BK, [D-Arg0,Hyp3,Thi5,D-Phe7,L-Pip8]BK, and Aaa[D-Arg0,Hyp3,Thi5,D-Phe7,L-Pip8]BK, were measured when immobilized onto a colloidal assembly of apparently randomly adhering Ag spheres with diameters of approximately 20 - 25 nm. The observed SERS bands corresponding to different vibrational modes of the molecule, attached to or near Ag, and the variations in these bands resulting from competitive interactions of the functional groups of the peptides with the SERS-active Ag surfaces were analyzed in this study. Briefly, it was shown that Pip, in generally in vertical orientation, and Thi, in the edge-on position, relative to the colloidal Ag surface interacted with this surface through their lone electron pairs on the nitrogen and sulfur atoms, respectively. The imide bond of the X-Pro peptide linkage and the guanidine group of Arg were involved in the adsorption process. In addition, it was demonstrated that the specific differences in the amino acid sequences slightly influenced the mode of adsorption. For example, Aaa in Aaa[D-Arg0,Hyp3,Thi5,8,L-Pip7]BK and Aaa[D-Arg0,Hyp3,Thi5,D-Phe7,L-Pip8]BK and D-Phe (vertical with respect to the colloidal Ag surface) in [D-Arg0,Hyp3,Thi5,D-Phe7,L-Pip8]BK, and Aaa[D-Arg0,Hyp3,Thi5,D-Phe7,L-Pip8]BK assisted in the adsorption of these peptides onto the colloidal Ag particles. To discuss these spectral alterations due to the different surface adsorption mechanisms of these peptides, the spectral changes were analyzed according to the adsorption process and Fourier-transform-Raman spectra. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In this paper, the surface-enhanced Raman scattering (SERS) spectra of the potent B2 bradykinin receptor antagonists, [D-Arg0,Hyp3,Thi5,8,L-Pip7]BK, Aaa[D-Arg0,Hyp3,Thi5,8,L-Pip7]BK, [D-Arg0,Hyp3,Thi5,D-Phe7,L-Pip8]BK, and Aaa[D-Arg0,Hyp3,Thi5,D-Phe7,L-Pip8]BK, were measured when immobilized onto a highly specific electrochemically roughened SERS-active Ag substrate characterized by the formation of a 50 - 150 nm Ag islands on its surface. The observed SERS bands corresponding to different vibrational modes of the molecule, attached to or near Ag, and the variations in these bands resulting from competitive interactions of the functional groups of the peptides with the SERS-active Ag surfaces and reorientation occurring over time of adsorption were analyzed in this study. Copyright © 2012 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In the present study, the effect of a conformational constraint introduced into the endomorphin-2 (Tyr-Pro-Phe-Phe-NH, EM-2) structure was studied using computational analysis and radioligand binding assay. EM-2 was modified by connecting nitrogen atoms of both phenylalanine residues by a methylene bridge. The obtained analog did not bind to the µ- or δ-opioid receptors in the in vitro studies. The computational analysis of this analog showed twisted, type IV turns and the absence of canonical β-turns typical for the EM-2 structure, which can be explained by the lack of hydrogen bonds involving Phe. Our results show that the introduction of chemical constraint in the EM-2 structure has a significant effect on opioid receptor affinity and in vitro bioactivity. [ABSTRACT FROM AUTHOR]

Continuing our efforts to obtain potent and selective analogues of AVP we synthesized and pharmacologically evaluated ten new compounds modified at position 2 with α-2-indanylglycine or its D-enantiomer (Igl or D-Igl, respectively). All the peptides were tested for pressor, antidiuretic, and in vitro uterotonic activities. We also determined the binding affinity of these compounds to human OT receptor. The Igl2 substitution resulted in a significant change of the pharmacological profile of the peptides. The new analogues were moderate or potent OT antagonists (pA2 values ranging from 7.19 to 7.98) and practically did not interact with V1a and V2 receptors. It is worth emphasizing that these new peptides were exceptionally selective. On the other hand, the D-Igl2 substituted counterparts turned out to be weak antagonists of the pressor response to AVP and displayed no antidiuretic activity. Some of the results were unexpected, e.g. dual activity in the rat uterotonic test in vitro: the D-Igl peptides showed a strong antioxytocic potency (pA2 values ranging from 7.70 to 8.20) at low concentrations and full agonism at high concentrations. The results provided useful information about the SAR of AVP analogues. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Using SPPS techniques, six new analogues of AVP and some of its agonists were synthesised. The peptides were designed by substitution of Phe at position 3 of AVP, [Mpa1] AVP (dAVP) and [Mpa1,Val4, D-Arg8]VP (dVDAVP) with L- or D-Pip, a non-coded α-imino acid, also called homoproline. Surprisingly enough, both the analogues of AVP and [Mpa1]AVP with identical substituents at position 2 turned out to be highly sensitive to TFA used for deprotection and cleavage of the synthesised peptides from the resin and it was the reason why we were not able to obtain these four peptides. The mechanisms of their fragmentation were proposed in this study. Unfortunately, all the new analogues were inactive in bioassays for the pressor, antidiuretic and uterotonic in vitro activities in the rat. Copyright © 2008 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The present work is part of our studies aimed at clarifying the influence of steric constraints in the N-terminal part of arginine vasopressin (AVP) and its analogs on the pharmacological activity of the resulting peptides. We describe the synthesis of eight new analogs of AVP or [3-mercaptopropionic acid (Mpa)1]AVP (dAVP) substituted at positions 2 and 3 or 3 and 4 with two diastereomers of 4-aminopyroglutamic acid. The steric constraints provided by this modification turned out, however, so strong that all the peptides were inactive in all of the bioassays (pressor, antidiuretic and uterotonic tests). Copyright © 2006 European Peptide Society and John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Continuing our efforts to obtain potent and selective analogues of AVP we synthesized and pharmacologically evaluated ten new compounds modified at position 2 with alpha-2-indanylglycine or its D-enantiomer (Igl or D-Igl, respectively). All the peptides were tested for pressor, antidiuretic, and in vitro uterotonic activities. We also determined the binding affinity of these compounds to human OT receptor. The Igl(2) substitution resulted in a significant change of the pharmacological profile of the peptides. The new analogues were moderate or potent OT antagonists (pA(2) values ranging from 7.19 to 7.98) and practically did not interact with V(1a) and V(2) receptors. It is worth emphasizing that these new peptides were exceptionally selective. On the other hand, the D-Igl(2) substituted counterparts turned out to be weak antagonists of the pressor response to AVP and displayed no antidiuretic activity. Some of the results were unexpected, e.g. dual activity in the rat uterotonic test in vitro: the D-Igl peptides showed a strong antioxytocic potency (pA(2) values ranging from 7.70 to 8.20) at low concentrations and full agonism at high concentrations. The results provided useful information about the SAR of AVP analogues.