Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics

Manning, M.; Misicka, A.; Olma, A.; Bankowski, K.; Stoev, S.; Chini, B.; Durroux, T.; Mouillac, B.; Corbani, M.; Guillon, G.

doi:10.1111/j.1365-2826.2012.02303.x

Cited by 429Neuroendocrine regulation and behaviorNeuropeptides and Animal PhysiologyChemical Synthesis and Analysis

Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics

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Manning, M., Misicka, A., Olma, A., Bankowski, K., Stoev, S., Chini, B., Durroux, T., Mouillac, B. +2 more·2012·Journal of Neuroendocrinology

DOI 10.1111/j.1365-2826.2012.02303.xPMC PMC3490377

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Abstract

We recently reviewed the status of peptide and nonpeptide agonists and antagonists for the V 1a , V 1b and V 2 receptors for arginine vasopressin (AVP) and the oxytocin receptor for oxytocin (OT). In the present review, we update the status of peptides and nonpeptides as: (i) research tools and (ii) therapeutic agents. We also present our recent findings on the design of fluorescent ligands for V 1b receptor localisation and for OT receptor dimerisation. We note the exciting discoveries regarding two novel naturally occurring analogues of OT. Recent reports of a selective VP V 1a agonist and a selective OT agonist point to the continued therapeutic potential of peptides in this field. To date, only two nonpeptides, the V 2 /V 1a antagonist, conivaptan and the V 2 antagonist tolvaptan have received Food and Drug Administration approval for clinical use. The development of nonpeptide AVP V 1a , V 1b and V 2 antagonists and OT agonists and antagonists has recently been abandoned by Merck, Sanofi and Pfizer. A promising OT antagonist, Retosiban, developed at Glaxo SmithKline is currently in a Phase II clinical trial for the prevention of premature labour. A number of the nonpeptide ligands that were not successful in clinical trials are proving to be valuable as research tools. Peptide agonists and antagonists continue to be very widely used as research tools in this field. In this regard, we present receptor data on some of the most widely used peptide and nonpeptide ligands, as a guide for their use, especially with regard to receptor selectivity and species differences.

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125I-OVTA and 125I-LVA bind selectively in rodents but have relatively high affinities for both oxytocin receptors and vasopressin receptor 1a in primates.
“Although these compounds bind selectively to their respective receptors in rodents, they have now been shown to exhibit relatively high affinities for both OXTR and AVPR1a in primates (27,28).”
From Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications (2016) · cites this paper as [28]
Comparing common ligands for human and rat OT and AVP receptors shows considerable species variation in pharmacological properties.
“Simply comparing the binding characteristics of the most common ligands for the human and rat OT and AVP receptors reveals considerable variation in pharmacological properties across species (28).”
From Comparative Perspectives on Oxytocin and Vasopressin Receptor Research in Rodents and Primates: Translational Implications (2016) · cites this paper as [28]
Studies using recombinant expression systems for human, rat, and mouse OT and AVP receptors have shown that only the human OTR is selective for OT by a standard criterion.
“For example, studies employing recombinant expression systems to examine selectivity of human, rat, and mouse OT and AVP receptors have shown that only the human OTR is selective for OT using a standard criterion [34; 35] (Table 1).”
From Cross-talk among oxytocin and arginine-vasopressin receptors: Relevance for basic and clinical studies of the brain and periphery (2018) · cites this paper as [35]
The limited information on distributions of OTR and V1aR in primate neural tissue is due in part to lower selectivity of radioligands for OTR and V1aR autoradiography in primates relative to rodents, and promiscuous binding profiles of both radioligands.
“The limited information on the distributions of OTR and V1aR in primate neural tissue is due in part to the lower selectivity for radioligands targeting OTR (125I-OVTA) and V1aR (125I-LVA) autoradiography, relative to high selectivity of radioligands for these receptors in rodents, as well as the promiscuous binding profile of both radioligands for OTR and V1aR (Freeman et al., 2014a, 2014b; Man”
From Neuropeptide diversity and the regulation of social behavior in New World primates (2016) · cites this paper as Manning et al., 2012
There was no difference in AVP levels, suggesting no peripheral cross-reactivity.
“There was also no difference in AVP levels, suggesting no peripheral cross-reactivity, which is more likely to occur with higher levels of oxytocin exposure.71”
From Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial (2017) · cites this paper as [71]

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Neuropeptide regulation of social behavior in a monogamous cichlid fish
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Chapter 15 Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands
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Vasopressin stimulates insulin release from islet cells through V1b receptors: a combined pharmacological/knockout approach
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Design and synthesis of highly selectivein vitroandin vivouterine receptor antagonists of oxytocin: comparisons with Atosiban
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Characterization of a Novel, Linear Radioiodinated Vasopressin Antagonist: An Excellent Radioligand for Vasopressin V 1a Receptors
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A radioiodinated linear vasopressin antagonist: A ligand with high affinity and specificity for V1a receptors
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Potent and selective antagonists of the antidiuretic responses to arginine-vasopressin based on modifications of [1-(.beta.-mercapto-.beta.,.beta.-pentamethylenepropionic acid), 2-D-isoleucine, 4-valine]arginine-vasopressin at position 4
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Oxytocin‐induced contractions within rat and rabbit ejaculatory tissues are mediated by vasopressin V1Areceptors and not oxytocin receptors
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Pharmacological characterization of the human vasopressin receptor subtypes stably expressed in Chinese hamster ovary cells
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Selectivity of d[Cha4]AVP and SSR149415 at human vasopressin and oxytocin receptors: evidence that SSR149415 is a mixed vasopressin V1b/oxytocin receptor antagonist
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Vaptans are not the mainstay of treatment in hyponatremia: perhaps not yet
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SSR126768A (4-Chloro-3-[(3 R)-(+)-5-chloro-1-(2,4-dimethoxybenzyl)-3-methyl-2- oxo-2,3-dihydro-1 H-indol-3-yl]-N-ethyl-N-(3-pyridylmethyl)-benzamide, Hydrochloride): A New Selective and Orally Active Oxytocin Receptor Antagonist for the Prevention of Preterm Labor
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A non‐natural amino acid for efficient incorporation into proteins as a sensitive fluorescent probe
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Identification, characterization and rescue of a novel vasopressin‐2 receptor mutation causing nephrogenic diabetes insipidus
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Pharmacological characterization of F‐180: a selective human V1a vasopressin receptor agonist of high affinity
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Original Fluorescent Ligand-Based Assays Open New Perspectives in G-Protein Coupled Receptor Drug Screening
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Oxytocin in the rat caudate nucleus influences pain modulation
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Targeting the oxytocin receptor to relax the myometrium
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Fluorescent Pseudo-Peptide Linear Vasopressin Antagonists: Design, Synthesis, and Applications,
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Oxytocin and vasopressin enhance synaptic transmission in the hypoglossal motor nucleus of young rats by acting on distinct receptor types
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Solid-phase synthesis and some pharmacological properties of 4-threonine analogs of vasopressins and vasotocin and of argininevasopressin and arginine-vasotocin
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Design of peptide oxytocin antagonists with strikingly higher affinities and selectivities for the human oxytocin receptor than atosiban
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Solid‐Phase Organic Tagging Resins for Labeling Biomolecules by 1,3‐Dipolar Cycloaddition: Application to the Synthesis of a Fluorescent Non‐Peptidic Vasopressin Receptor Ligand
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C-Terminal deletions in antagonistic analogs of vasopressin that improve their specificities for antidiuretic (V2) and vasopressor (V1) receptors
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Arginine vasopressin gene expression changes within the nucleus accumbens during environment elicited cocaine-conditioned response in rats
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Research works printed but not linked: 3

[9]Manning M Sawyer WH Schrier R Development of Selective Agonists and Antagonists of Vasopressin and Oxytocin, Vasopressin 1985 New York, NY Raven Press 131 144
[18]Lebl M Jost K Lebl M Brtnik F Analogs with inhibitory properties Handbook of Neurohypophyseal Hormone Analogs 1988 2 Boca Raton, FL CRC Press 17 72 Part 1, Part 2. 127–267
[38]Wisniewski K Galyean R Schteingart CD Tariga H Croston G Alagarsamy S Riviere PJM Lebl M Meldal M Knud J Jensen KJ Høeg-Jensen T Synthesis and in vitro characterization of new potent and selective oxytocin receptor agonist Peptides 2010 2010 306 307 Proc of the 31st European Peptide Symposium, The European Peptide Society

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“However, this study used [3H] OT and, like [3H] VP, [3H] OT may not exclusively bind OTR (Mouillac et al., 1995; Manning et al., 2012), and thus possibly may mask potential sex differences in OTR binding.”
Method
Neuromodulation by Oxytocin and Vasopressin
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Orally Absorbed Cyclic Peptides
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“For example, if central AVP levels are higher in men, additional exogenous AVP could saturate AVP receptors and cross-react with OT receptors (Manning et al., 2012; Young and Flanagan-Cato, 2012) and this, in turn, could drive increases in activity in regions involved in reward and bonding.”
Background
Assembling the puzzle: pathways of oxytocin signaling in the brain
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Insular cortex mediates approach and avoidance responses to social affective stimuli
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Oxytocin and vasopressin: powerful regulators of social behavior
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“Simply comparing the binding characteristics of the most common ligands for the human and rat OT and AVP receptors reveals considerable variation in pharmacological properties across species (28).”
Background
A spatiotemporal profile of in vivo cerebral blood flow changes following intranasal oxytocin in humans
Paloyelis, Y., Doyle, O. M., Zelaya, F. O., Maltezos, S., Williams, S. C., Fotopoulou, A., & Howard, M. A. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2014.10.005 · Cited by 187 · see citing works
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“Although the behavioral effects of OTare widely assumed to mediated by central OXTR, OT does cross react with the AVP receptors and vice versa (Manning et al., 2012), and some of the behavioral effects of OT are mediated by AVPR1A (Schorscher-Petcu et al.”
Background
Helping oxytocin deliver: considerations in the development of oxytocin-based therapeutics for brain disorders
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Oxytocin receptors are expressed on dopamine and glutamate neurons in the mouse ventral tegmental area that project to nucleus accumbens and other mesolimbic targets
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Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents☆
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REVIEW ARTICLE Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics
(2016)

Authors: Manning, M., Misicka, A., Olma, A., Bankowski, K., Stoev, S., Chini, B., Durroux, T., Mouillac, B., Corbani, M., & Guillon, G.
Affiliations: University of Toledo (US)
University of Warsaw (PL)
Lodz University of Technology (PL)
Centre National de la Recherche Scientifique (FR)
Corresponding author: Manning, M.
ORCID: Misicka, A.
Chini, B.
Durroux, T.
Mouillac, B.
Corbani, M.
Venue: Journal of Neuroendocrinology
Publisher: Wiley
Published: 2012-03-26
Volume: 24
Issue: 4
Pages: 609-628
ISSN: 0953-8194 (ISSN-L)
1365-2826
DOI: 10.1111/j.1365-2826.2012.02303.x
PMC: PMC3490377
OpenAlex: W1803779312
Cited by: 423
References: 244
Citations by year: 2026: 14 · 2025: 20 · 2024: 22 · 2023: 25 · 2022: 32 · 2021: 36 · 2020: 31 · 2019: 40 · 2018: 34 · 2017: 35 · 2016: 28 · 2015: 29 · 2014: 38 · 2013: 30 · 2012: 8
FWCI: 4.80
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Neuroendocrinology (publishedVersion)
PubMed Central (publishedVersion, cc-by)
PubMed (publishedVersion)
Funders: Institut National de la Santé et de la Recherche Médicale
Ministero dell’Istruzione, dell’Università e della Ricerca
Centre National de la Recherche Scientifique
National Institute of General Medical Sciences (GM25280, R01GM025280)
Topics: Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chemical Synthesis and Analysis
Keywords: oxytocin, vasopressin, vasopressin receptor, oxytocin receptor, V1a receptor, V1b receptor, V2 receptor, peptide agonists, peptide antagonists, conivaptan, tolvaptan, fluorescent ligands, receptor localization, receptor dimerization, oxytocin analogues, receptor selectivity, species differences
MeSH terms: Animals, Arginine Vasopressin, Clinical Trials as Topic, Drug Evaluation, Preclinical, Humans, Oxytocin, Structure-Activity Relationship, Receptors, Vasopressin, Receptors, Oxytocin, Antidiuretic Hormone Receptor Antagonists

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Oxytocin and Vasopressin Agonists and Antagonists as Research Tools and Potential Therapeutics

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