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
Gene expression studies advance our understanding of the effects of stress and glucocorticoids on brain function and give a new direction to animal welfare research. In this context, the presence of messenger RNAs (mR...
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Gene expression studies advance our understanding of the effects of stress and glucocorticoids on brain function and give a new direction to animal welfare research. In this context, the presence of messenger RNAs (mRNAs) for corticotrophin releasing hormone (CRH) and vasopressin (vp) in the porcine hypothalamus has recently been documented. This study investigated the expression of CRH, vr and ionotropic glutamate receptor (iGluR) subunit mRNAS in the brains of pigs treated with the synthetic glucocorticoid dexamethasone (Dex 5 mg kg(-1) i.v.). In the hypothalamus, VP, but not CRH, mRNA was reduced 3 hours after Dex. In the hippocampus, expression of mRNAs for some iGluR subunits appeared to he differentially regulated 6 hours after Dex. In addition, CRH message was detected in the hippocampus and significantly upregulated in the CA1 region 3 hours after Dex. The relevance of these findings to stress neurobiology of the growing, pig is discussed. (C) 2000 Harcourt Publishers Ltd.
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