Synthetic oxytocin and vasopressin agonists and antagonists have become important tools for research and were instrumental in the identification of the four known receptor subtypes, V-1a, V-2, V-1b (V-3) and oxytocin,...
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Synthetic oxytocin and vasopressin agonists and antagonists have become important tools for research and were instrumental in the identification of the four known receptor subtypes, V-1a, V-2, V-1b (V-3) and oxytocin, of these peptide hormones. However, the relative lack of receptor selectivity, particularly of the antagonists, has limited their usefulness as experimental probes and their potential as therapeutic agents. We now present some findings from our continuing studies aimed at the design of more selective oxytocin and vasopressin agonists and antagonists and a structure-activity relationship update on our recently discovered novel hypotensive vasopressin peptides. Bioassays have been, and continue to be, of critical importance in leading to the discovery of the novel agonists, antagonists and hypotensive peptides reported here. This paper highlights three main aspects of these studies. (1) Replacement of the tyrosine(2) and/or phenylalanine(3) residues in the V-2 agonist deamino,[Val(4), D-Arg(8)]arginine-vasopressin (dVDAVP) by thienylalanine resulted in selective V-2 agonists with strikingly high potencies. However, the peptide solutions were unstable and lost activity over time. These highly potent V-2 agonists, which are devoid of vasopressor activity, are promising leads for improving drugs for treating diabetes insipidus, enuresis and coagulation disorders. (2) Diaminopropionic acid and diaminobutyric acid substitution at position-5 in oxytocin and in V-1a antagonists yielded, respectively, the first specific antagonist for the oxytocin receptor, desGly-NH2,d(CH2)(5)[D-Trp(2),Thr(4),Dap(5)]OVT and the first specific antagonist for the vasopressin V-1a receptor, d(CH2)(5)[Tyr(Me)(2),Dab(5)]AVP. The availability of single receptor subtype-specific or selective antagonists will enhance our ability to delineate receptor functions. Utilising these new receptor specific probes, we were able to show that the uterotonic action of vasopressin is mediated princ
This presentation will trace the serendipitous discovery of novel vasopressin (VP) hypotensive agonists d(CH(2))(5)[D-Tyr(Et)(2),X(3)]VAVP (where X = Arg, Lys). These peptides were uncovered as part of an ongoing prog...
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This presentation will trace the serendipitous discovery of novel vasopressin (VP) hypotensive agonists d(CH(2))(5)[D-Tyr(Et)(2),X(3)]VAVP (where X = Arg, Lys). These peptides were uncovered as part of an ongoing program aimed at the design of potent and selective VP antidiuretic (V(2) receptor) antagonists. We will also present highlights of our subsequent preliminary studies seeking (i) to design high affinity radioiodinatable ligands for the localization and characterization of the putative VP vasodilatory (V(1c) ?) receptor;(ii) to identify the structural features of selective and non-selective cyclic and linear VP and oxytocin (OT) antagonists of the V(2) receptor, the vascular (V(1a)) receptor and of the uterine (OT) receptor required for hypotensive agonism and;(iii) to enhance hypotensive potency. These novel VP hypotensive agonists could serve as valuable research tools in studies on the roles of VP in blood pressure regulation and may also lead to the development of a new class of therapeutically useful antihypertensives.
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