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Cited by 41Neuroendocrine regulation and behaviorChemical Synthesis and AnalysisNeuropeptides and Animal Physiology

Discovery and design of novel and selective vasopressin and oxytocin agonists and antagonists: the role of bioassays

Chan, W. Y., Wo, Nga Ching, Stoev, Stoytcho, Cheng, Ling Ling, Manning, Maurice·2000·Experimental Physiology
DOI 10.1111/j.1469-445x.2000.tb00003.x
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Abstract

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‐NH 2,d(CH 2)5[D‐Trp 2, Thr 4, Dap 5]OVT and the first specific antagonist for the vasopressin V 1a receptor, d(CH 2)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 thatthe uterotonic action of vasopressin is mediated principally by oxytocin and not by V 1a receptors. (3) Replacement of the phenylalanine 8 residue in the V 1a/V 2/oxytocin antagonist, d(CH 2)5[D‐Tyr(Et)2, Val 4]AVP, with arginine 3 yielded the novel, selective, hypotensive vasopressin peptide, d(CH 2)5[D‐Tyr(Et)2, Arg 3, Val 4]AVP (Peptide I). Bioassay characterisations of Peptide I show that its vasodepressor action is independent of the peripheral autonomic, bradykinin, nitric oxide and prostaglandin systems and is not mediated by the known classical oxytocin and vasopressin receptors. These findings suggest the existence of a new vasopressin receptor subtype that may be relevant to the vasodilating action of vasopressin in regional vascular beds. Iodinatable hypotensive peptides have been synthesised and could be developed as markers for the putative new receptor. Ongoing structure‐activity relationship studies on Peptide I have led to more potent and selective hypotensive peptides for use as new research tools and as leads for the development of a new class of antihypertensive agents.

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  • By the end of the 20th century, bioassays were still of critical importance in the discovery of novel antagonists and agonists of vasopressin and oxytocin because biological activity cannot be inferred from structure alone.

    “By the end of the 20th century, bioassays were still ‘of critical importance’ in the discovery of novel antagonists and antagonists of vasopressin and oxytocin because biological activity cannot be inferred from structure alone 75.”

    From Measuring Oxytocin and Vasopressin: Bioassays, Immunoassays and Random Numbers (2016) · cites this paper as [75]

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Authors
Chan, W. Y., Wo, N. C., Stoev, S., Cheng, L. L., & Manning, M.
Affiliations
Cornell University (US)
Corresponding author
Chan, W. Y.
ORCID
Venue
Experimental Physiology
Publisher
Wiley
Published
2000-03
Volume
85
Issue
s1
Pages
7S-18S
ISSN
  • 0958-0670 (ISSN-L)
  • 1469-445X
DOI
10.1111/j.1469-445x.2000.tb00003.x
OpenAlex
W2075343329
Cited by
41
References
49
Citations by year
2023: 1 · 2021: 2 · 2020: 1 · 2019: 1 · 2016: 1 · 2015: 3 · 2014: 1 · 2012: 2
FWCI
1.09
Type
journal article
Language
en
Open access
closed
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 1860 d)
Locations
  • Experimental Physiology (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (GM25280, R01GM025280)
Topics
  • Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Keywords
vasopressin receptor antagonists, oxytocin receptor, vasopressin V1a receptor, V2 receptor, structure-activity relationship, diaminopropionic acid, diaminobutyric acid, receptor selectivity
MeSH terms
Amino Acid Sequence, Animals, Antihypertensive Agents, Biological Assay, Oxytocin, Vasopressins, Drug Design

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