Several new synthetic analogs of the oxytocin antagonist [l-deaminopenicillamine]oxytocin have been prepared and tested for their abilities to inhibit responses to oxytocin by the isolated rat uterus in the absence and presence of Mg++, by the rat uterus in situ, and by the rat mammary gland in situ. Substituting 2-O-methyltyrosine in [1-deaminopenicillamine] oxytodn strikingly enhances antagonism of all uterine responses, and [1-deaminopenicillamine, 2-O-methyltyrosine]oxytocin and its 4-threonine analog are also potent inhibitors of the milk ejection response. Substituting 2-phenylalanine in [1-deaminopenicillamine]oxytocin also enhances antagonistic activities in all uterine assays, but [1-deaminopenicillamine, 2-phenylalaninejoxytocin retains agonistic activity on milk ejection assays. From these studies we can conclude that changes in the 1-position (1-deaminopenicillamine substitution) and the 2-position (2-O-methyltyrosine or 2-phenylalanine substitution) can have additive effects on antagonistic activities. Substitution of an 8-ornithine also enhances inhibitory potency in vivo, and this effect may also be additive to those of the substitutions in 1- and 2-positions. These findings provide many clues that may lead to the design of even more effective antagonists; several of the analogs reported here appear to be the most effective antagonists of oxytocin in vivo yet reported and may be useful agents in further studies on the physiological functions of endogenous oxytocin. (Endocrinology106: 81, 1980)
The design and development of selective agonists acting at the OT (oxytocin)/AVP (vasopressin) receptors has been and continues to be a difficult task because of the great similarity among the different receptor subtypes as well as the high degree of chemical similarity between the active ligands. In recent decades, at least a thousand synthetic peptides have been synthesized and examined for their ability to bind to and activate the different OT/AVP receptors; an effort that has led to the identification of several receptor subtype-selective agonists in the rat. However, owing to species differences between rat and human AVP/OT receptors, these peptides do not exhibit the same selectivities in human receptor assays. Furthermore, the discovery of receptor promiscuity, which is the ability of a single receptor subtype to couple to several different G-proteins, has led to the definition of a completely new class of compounds, referred to here as coupling-selective ligands, which may activate, within a single receptor subtype, only a specific signalling pathway. Finally, the accumulating evidence that GPCRs (G-protein-coupled receptors) do not function as monomers, but as dimers/oligomers, opens up the design of another class of specific ligands, bivalent ligands, in which two agonist and/or antagonist moieties are joined by a spacer of the appropriate length to allow the simultaneous binding at the two subunits within the dimer. The pharmacological properties and selectivity profiles of these bivalent ligands, which remain to be investigated, could lead to highly novel research tools and potential therapeutic agents.
Experiments were performed to determine the role of vasopressin in deoxycorticosterone (DOC)-salt hypertension. In order to determine if vasopressin is necessary for the development of DOC-salt hypertension, rats with hereditary diabetes insipidus (DI) and normal Long-Evans rats (LE) were unilaterally nephrectomized, treated with DOC Pivalate (30 mg/kg . week) and given saline to drink for 8 weeks. A second group of DI rats were unilaterally nephrectomized, but received no treatment. Systolic blood pressure (SBP) increased 40 mm Hg in the LE group (p less than 0.01) but failed to increase significantly in either DI group. Urinary excretion of vasopressin (UADHV) and SBP were measured in unilaterally nephrectomized LE rats treated with DOC and salt (DOC-LE), salt alone (NaCl-LE) and untreated rats (H2O-LE). The UADHV was elevated in DOC-LE (p less than 0.01) and NaCl-LE (p less than 0.05), but only the DOC-LE rats became hypertensive. Finally, the I.V. injection of analogs of vasopressin, which block its pressor but not antidiuretic activity, lowered mean arterial blood pressure 27 +/- 5 mm Hg in 11 conscious DOC-salt hypertensive rats. It is concluded that vasopressin plays a major role as a pressor agent in both the onset and maintenance of DOC-salt hypertension.
SummaryIntravenous infusion of [1-Deaminopenicillamine, 4-valine, 8-D-arginine]-vasopressin (dPVDAVP) inhibited the mesenteric vasoconstrictor response to arginine vasopressin in cats but the compound initiated little or no vasodilatation when administered alone in hypophysectomized cats and it failed to inhibit the mesenteric vasoconstrictor response to angiotensin II. The results are consistent with the interpretation that dPVDAVP is an antagonist of the vasoconstrictor activity of arginine vasopressin.
This paper describes further pharmacological characterization of the decidual prostaglandin-releasing oxytocin receptors and the myometrial uterotonic oxytocin receptors in the uterus of the pregnant rat. The effects of oxytocin, arginine-vasopressin and their related agonists and antagonists on the release of PGF2α were studied in vitro on isolated uteri from rats on day 19–20 of pregnancy that had been incubated in Krebs buffer, pH 7.4, at 37°C. The concentration of PGF2α in the media was measured using specific radioimmunoassays. It was found that the decidual and myometrial oxytocin receptors exhibit different ligand specificities. Of the agonists tested, oxytocin and arginine-vasopressin stimulated PGF2α release in a dose-dependent manner. Arginine-vasopressin has only 3% of the uterotonic potency of oxytocin, but was found to have 16% of its PGF2α-releasing activity. [4-Threonine, 7-glycine]oxytocin, a highly potent and selective uterotonic oxytocin analogue, had no detectable prostaglandin-releasing activity at a dosage 30 times higher than oxytocin. However, 1-deamino-[8-d-arginine]vasopressin, a highly potent and selective antidiuretic arginine-vasopressin analogue, which has only 10% of the uterotonic activity of arginine-vasopressin, was as potent as arginine-vasopressin in prostaglandin-releasing activity. Of the oxytocin antagonists tested, it was confirmed that 1-penicillamine, 2-O-methyl-tyrosine, 4-threonine]ornithine-vasotocin and its close congener [1-penicillamine, 2-p-methyl-phenylalanine, 4-threonine]ornithine-vasotocin are partial oxytocin antagonists and that 9-desglycinamide-[1-(β-mercapto-β-β-cyclopentamethylenepropionic acid)2-O-methyl-tyrosine, 4-threonine]ornithine-vasotocin, [1-(β-mercapto-β-β-cyclopentamethylenepropionic acid)2-O-methyl-tyrosine, 4-threonine]ornithine-vasotocin and 1-deamino-penicillamine [2-O-methyl-tyrosine]ornithine-vasotocin are full oxytocin antagonists. The two partial oxytocin antagonists blocked the uterotonic action of oxytocin but had agonistic activity on decidual receptors, stimulating release of PGF2α. The full oxytocin antagonists blocked both the uterotonic and PGF2α-releasing actions of oxytocin. Thus, the myometrial and decidual oxytocin receptors have different ligand specificities for agonists and antagonists. We propose that the two uterine oxytocin receptor subtypes be designated as OT1a for the myometrial uterotonic receptors and OT1b for the endometrial or decidual prostaglandin-releasing receptors.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTSolid-phase synthesis and some pharmacological properties of 8-phenylalanine-oxytocinJ. W. M. Baxter, M. Manning, and W. H. SawyerCite this: Biochemistry 1969, 8, 9, 3592–3597Publication Date (Print):September 1, 1969Publication History Published online1 May 2002Published inissue 1 September 1969https://pubs.acs.org/doi/10.1021/bi00837a015https://doi.org/10.1021/bi00837a015research-articleACS PublicationsRequest reuse permissionsArticle Views41Altmetric-Citations16LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose Get e-Alerts
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