Oxytocin receptor agonist

Oxytocin, an example of a peptide oxytocin receptor agonist.
LIT-001, an example of a small-molecule oxytocin receptor agonist.

An oxytocin receptor agonist is a compound that acts as an agonist of the oxytocin receptor.[1][2] They include peptides like oxytocin and carbetocin and small-molecules like LIT-001 and LIT-002.[1][2] Peptide oxytocin receptor agonists are used medically to induce labor, promote lactation, and for certain other uses.[3]

Oxytocin receptor agonists are of theoretical interest for the potential treatment of neuropsychiatric disorders with social symptoms, such as autism, social anxiety, and psychopathy.[1][2][4] Small-molecule oxytocin receptor agonists are considered to be more promising for such uses due to better potential pharmacokinetic profiles, such as blood–brain barrier permeability, elimination half-lives, and oral bioavailability.[1][2]

The entactogen MDMA robustly increases oxytocin levels, by 4- to 8-fold, and this is thought to be involved in its entactogenic effects, including its euphoric, anxiolytic, and prosocial effects.[5][6][7][8] In people with arginine vasopressin deficiency (central diabetes insipidus), who also have oxytocin deficiency, MDMA fails to elevate oxytocin levels and shows greatly blunted entactogenic effects.[9][8][10][11] Accordingly, carbetocin partially substitutes for MDMA in drug discrimination tests in rodents, whereas the peptide oxytocin receptor antagonist atosiban interfered with MDMA discrimination.[12][13] In addition, oxytocin receptor antagonists have been found to block the prosocial effects of MDMA in rodents.[5][7][14][15]

Social isolation has been found to decrease oxytocin receptor levels in rodents, whereas levels of oxytocin were unchanged.[16] The decreased oxytocin receptor levels were associated with behavioral changes including increased aggression and anxiety-like behavior, hyperactivity, and diminished social behaviors and memory.[16] Exogenous administration of oxytocin receptor agonists like oxytocin or TGOT was able to partially reverse the behavioral changes.[16]

List of oxytocin receptor agonists

Peptides

Non-peptides

  • CA7 – among smallest-known oxytocin receptor agonists; considerable selectivity over the vasopressin V1A receptor[17][18]
  • KNX-200 (KNX200) – series; chemical structure(s) not yet disclosed[19][20]
  • LIT-001 — improved social deficits in mice; non-selective over vasopressin receptors
  • LIT-002 – highly potent, under formal development
  • TC OT 39 – non-selective over vasopressin receptors
  • WAY-267,464 – anxiolytic in mice; possibly non-selective over vasopressin receptors[21][22][23]
  • WJ0679 – among smallest-known oxytocin receptor agonists; produces prosocial effects in rodents[17][18]

In April 2025, a series of novel and highly potent small-molecule oxytocin receptor agonists with high selectivity over the vasopressin V1A receptor (up to >5,000-fold) were patented and described.[24][25]

Unknown

Indirect

See also

References

  1. 1 2 3 4 Nashar PE, Whitfield AA, Mikusek J, Reekie TA (2022). "The Current Status of Drug Discovery for the Oxytocin Receptor". Oxytocin. Methods Mol Biol. Vol. 2384. pp. 153–174. doi:10.1007/978-1-0716-1759-5_10. ISBN 978-1-0716-1758-8. PMID 34550574. S2CID 239090096.
  2. 1 2 3 4 Gulliver D, Werry E, Reekie TA, Katte TA, Jorgensen W, Kassiou M (January 2019). "Targeting the Oxytocin System: New Pharmacotherapeutic Approaches". Trends in Pharmacological Sciences. 40 (1): 22–37. doi:10.1016/j.tips.2018.11.001. hdl:1959.4/unsworks_81554. PMID 30509888. S2CID 54559394.
  3. ↑ Viero C, Shibuya I, Kitamura N, Verkhratsky A, Fujihara H, Katoh A, et al. (October 2010). "REVIEW: Oxytocin: Crossing the bridge between basic science and pharmacotherapy". CNS Neuroscience & Therapeutics. 16 (5): e138–56. doi:10.1111/j.1755-5949.2010.00185.x. PMC 2972642. PMID 20626426.
  4. ↑ Ferreira-Nascimento S, Freire F, Prata D (2025). "Psychophysiology of facial emotion recognition in psychopathy dimensions and oxytocin's role: A scoping review". PLOS ONE. 20 (7) e0327764. Bibcode:2025PLoSO..2027764F. doi:10.1371/journal.pone.0327764. PMC 12310049. PMID 40737230.
  5. 1 2 Dunlap LE, Andrews AM, Olson DE (October 2018). "Dark Classics in Chemical Neuroscience: 3,4-Methylenedioxymethamphetamine". ACS Chemical Neuroscience. 9 (10): 2408–2427. doi:10.1021/acschemneuro.8b00155. PMC 6197894. PMID 30001118.
  6. ↑ Vaslavski A, Gross AH, Israel S, Peled-Avron L (October 2025). "The effect of MDMA administration on oxytocin concentration levels: systematic review and a multilevel meta-analysis in humans". Neuroscience and Biobehavioral Reviews. 177 106324. doi:10.1016/j.neubiorev.2025.106324. PMID 40812728. These foundational mechanistic insights were soon validated in human studies around 2009–2012, showing acute MDMA administration (~1.5 mg/kg) raises plasma oxytocin several-fold—typically from ~20 pg/mL to over 80 pg/mL—and correlates with enhanced sociability, emotional openness, and reduced fear recognition (Dumont et al., 2009; Hysek, Domes, et al., 2012a). [...] The administration of MDMA can elevate oxytocin levels substantially, often reported as a fourfold increase in some contexts (Dumont et al., 2009).
  7. 1 2 Kamilar-Britt P, Bedi G (October 2015). "The prosocial effects of 3,4-methylenedioxymethamphetamine (MDMA): Controlled studies in humans and laboratory animals". Neuroscience and Biobehavioral Reviews. 57: 433–446. doi:10.1016/j.neubiorev.2015.08.016. PMC 4678620. PMID 26408071.
  8. 1 2 Atila C, Refardt J, Christ-Crain M (March 2026). "Arginine Vasopressin Deficiency and Oxytocin Deficiency in the Endocrine Clinic". The Journal of Clinical Endocrinology and Metabolism. 111 (4): 922–937. doi:10.1210/clinem/dgaf651. PMC 13017940. PMID 41363127. A recent study used 3,4-methylenedioxymethamphetamine (MDMA) as a pharmacological provocation agent (196, 197). A single 100-mg dose of MDMA led to an 8-fold increase in plasma OXT in healthy individuals, but elicited no OXT increase in patients with AVP deficiency (197). Correspondingly, controls experienced characteristic psychoactive effects such as empathy, trust, openness, and reduced anxiety, whereas patients displayed blunted or absent responses, both emotionally and physiologically.
  9. ↑ Vogt SB, Liechti ME (2025). "Clinical Pharmacology". In Nutt DJ, Thurgur H (eds.). Psychedelics in Psychiatry. International Review of Neurobiology. Vol. 181. London: Academic Press. pp. 99–148. doi:10.1016/bs.irn.2025.02.003. ISBN 978-0-443-34386-5. PMID 40541320. The MDMA-induced release of oxytocin also contributes to acute positive emotional effects of MDMA, including enhancing trust and emotional empathy and reducing fear perception (Atila et al., 2023; Dumont et al., 2009; Francis et al., 2016; Hysek et al., 2014; Kirkpatrick et al., 2014). For example, the importance of oxytocin in mediating MDMA's effects was demonstrated in a study of patients with arginine vasopressin deficiency (also known as central diabetes insipidus) who also had been shown to have a deficit in oxytocin (Atila et al., 2023). In these patients, MDMA failed to elevate oxytocin levels, and it also markedly reduced empathetic and anxiolytic effects compared with healthy controls.
  10. ↑ Atila C, Refardt J, Christ-Crain M (August 2024). "Arginine vasopressin deficiency: diagnosis, management and the relevance of oxytocin deficiency". Nature Reviews. Endocrinology. 20 (8): 487–500. doi:10.1038/s41574-024-00985-x. PMID 38693275. To this purpose, MDMA (also known as the recreational drug 'ecstasy') was assessed in a 2023 study as a stimulus for oxytocin9 (Fig. 4). MDMA increases peripheral oxytocin levels and central oxytocin-mediated behavioural effects, which are associated with its empathic and prosocial profile. These effects include increased closeness and openness to others, enhanced trust, elevated happiness and an overall sense of well-being102–105. In the 2023 study, patients with AVP deficiency showed no difference in basal plasma oxytocin levels compared with matched healthy control individuals. In response to MDMA administration, control individuals showed an eight-fold increase in plasma levels of oxytocin, whereas no response was seen in patients9. In patients, psychoactive effects induced by MDMA (for example, 'good effect', 'liking effect' or 'feeling high') were either blunted or absent compared with control individuals (Fig. 4). [...] Thus, in contrast to the predicted effects in control individuals, nearly all of the psychoactive effects of MDMA were either blunted or absent in patients9.
  11. ↑ Atila C, Holze F, Murugesu R, Rommers N, Hutter N, Varghese N, et al. (July 2023). "Oxytocin in response to MDMA provocation test in patients with arginine vasopressin deficiency (central diabetes insipidus): a single-centre, case-control study with nested, randomised, double-blind, placebo-controlled crossover trial". The Lancet. Diabetes & Endocrinology. 11 (7): 454–464. doi:10.1016/S2213-8587(23)00120-1. PMID 37192642.
  12. ↑ Broadbear JH, Kabel D, Tracy L, Mak P (April 2014). "Oxytocinergic regulation of endogenous as well as drug-induced mood". Pharmacology, Biochemistry, and Behavior. 119: 61–71. doi:10.1016/j.pbb.2013.07.002. PMID 23872370.
  13. ↑ Broadbear JH, Tunstall B, Beringer K (April 2011). "Examining the role of oxytocin in the interoceptive effects of 3,4-methylenedioxymethamphetamine (MDMA, 'ecstasy') using a drug discrimination paradigm in the rat". Addiction Biology. 16 (2): 202–214. doi:10.1111/j.1369-1600.2010.00267.x. PMID 21070509.
  14. ↑ Wronikowska-Denysiuk O, Mrozek W, Budzyńska B (February 2023). "The Role of Oxytocin and Vasopressin in Drug-Induced Reward-Implications for Social and Non-Social Factors". Biomolecules. 13 (3): 405. doi:10.3390/biom13030405. PMC 10046619. PMID 36979340.
  15. ↑ Kuteykin-Teplyakov K, Maldonado R (November 2014). "Looking for prosocial genes: ITRAQ analysis of proteins involved in MDMA-induced sociability in mice". European Neuropsychopharmacology. 24 (11): 1773–1783. doi:10.1016/j.euroneuro.2014.08.007. hdl:10230/23309. PMID 25241352.
  16. 1 2 3 Krimberg JS, Lumertz FS, Orso R, Viola TW, de Almeida RM (March 2022). "Impact of social isolation on the oxytocinergic system: A systematic review and meta-analysis of rodent data". Neuroscience and Biobehavioral Reviews. 134 104549. doi:10.1016/j.neubiorev.2022.104549. hdl:10923/25707. PMID 35074312.
  17. 1 2 Nashar PE, Whitfield AA, Mikusek J, Reekie TA (2022). "The Current Status of Drug Discovery for the Oxytocin Receptor". Methods in Molecular Biology. 2384. Clifton, N.J.: 153–174. doi:10.1007/978-1-0716-1759-5_10. PMID 34550574. Recent work by Kassiou and colleagues [102] led to the identification of a key motif relevant to functional oxytocin receptor binding. From this motif, they were able to develop a number of nonpeptide OTR agonists, which were considerably smaller than any previously documented, with their lead drug-like molecule WJ0679 (Fig. 7) possessing a molecular weight about 60% that of LIT-001. In behavioral tests, intraperitoneal injection of WJ0679 was demonstrated to increase the amount of time mice spent in close physical contact with one another, indicating prosocial effects [102]. While WJ0679 was demonstrated to show only a mild form of partial agonism for the OTR, making it a less than ideal potential therapeutic, further characterization of other compounds described in the patent has revealed structurally related compound CA7 to be a potent OTR agonist with considerable selectivity over the V1aR, where it exerts no functional activity (Table 2)[102]. While additional details on in vivo activity have yet to be published, with the characterization and development of this group of compounds, their smaller size and receptor potency make them very promising, both as potential therapeutics and as analytical tools for probing the OTR. Given that compounds such as CA7 show activity despite lacking a tail component like those seen in TC OT 39, WAY-267,464 and LIT-001 confound rational design of OTR agonists. [...] Fig. 7 Structural motif and two oxytocin agonist compounds identified by Kassiou and colleagues [102]. In the structural motif, X can be any of a number of substituted or unsubstituted cyclic functional groups as demonstrated by WJ0679 and CA7
  18. 1 2 WO 2018107216, Kassiou M, Jorgensen W, Werry E, Reekie T, Bowen M, Mcgregor I, "Non-peptide oxytocin receptor agonists", published 12 December 2017, assigned to University of Sydney
  19. ↑ Sami T (13 January 2026). "Kinoxis and Boehringer to develop oxytocin-targeting treatments for social dysfunction in $181M deal". BioWorld. Retrieved 13 January 2026.
  20. ↑ Spotlight Showcases: Kinoxis Therapeutics Pty Ltd. 5th Annual Neruoscience Innovation Forum for Business Development, Licensing & Investment 22nd–23rd March 2022, Digital Conference. March 2022. Kinoxis' lead candidate (KNX100) is being developed for the mitigation of opioid withdrawal symptoms. KNX100 has a novel, undisclosed mechanism of action and a Phase I clinical trial has commenced under a US IND. The company is also exploring other indications for its lead compound, KNX100, as promising preclinical results have been achieved in animal models of cocaine, methamphetamine, nicotine, and alcohol use disorders, as well as models of agitation and aggression. [...] Kinoxis' second series of compounds target the oxytocin receptor, through either selective partial agonism or positive allosteric modulation. The brain oxytocin system has been identified as perhaps the most important molecular target for regulating social behaviour and is therefore a major target of interest for treating a wide range of mental disorders. The development of these compounds will be focused on treating conditions that feature social dysfunction as a core symptom, such as neurodevelopmental disorders (including autism spectrum disorder), social anxiety disorder, dementia (including Alzheimer's disease), PTSD and schizophrenia. The KNX200 series of oxytocin receptor partial agonists are undergoing candidate selection stage using several pre-clinical animal disease models (Alzheimer's, PTSD, ASD) and the KNX300/400 series of oxytocin receptor positive allosteric modulators are undergoing lead optimisation.
  21. ↑ Manning M, Stoev S, Chini B, Durroux T, Mouillac B, Guillon G (2008). "Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: Research tools and potential therapeutic agents☆". Peptide and non-peptide agonists and antagonists for the vasopressin and oxytocin V1a, V1b, V2 and OT receptors: research tools and potential therapeutic agents. Progress in Brain Research. Vol. 170. pp. 473–512. doi:10.1016/S0079-6123(08)00437-8. ISBN 978-0-444-53201-5. PMID 18655903.
  22. ↑ US application 2007/0117794, Rahman Z, Resnick L, Rosenzweig-Lipson SJ, Ring RH, "Methods of treatment using oxytocin receptor agonists", published 2007-05-24, issued 1841-03-16, assigned to Wyeth Corp
  23. ↑ Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R, et al. (January 2010). "Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist". Neuropharmacology. 58 (1): 69–77. doi:10.1016/j.neuropharm.2009.07.016. PMID 19615387. S2CID 8592340.
  24. ↑ Li Y, Liang SH (May 2025). "Novel Nonpeptide as Oxytocin Receptor Agonist". ACS Medicinal Chemistry Letters. 16 (5): 750–751. doi:10.1021/acsmedchemlett.5c00191. PMC 12067107. PMID 40365388.
  25. ↑ Song Z, Liang SH (May 2025). "Novel Tetrahydrobenzo[b]pyrazolo[3,4-e][1,4]diazepine Compounds as Oxytocin Receptor Agonists for Treating Autism Spectrum Disorders". ACS Medicinal Chemistry Letters. 16 (5): 752–753. doi:10.1021/acsmedchemlett.5c00190. PMC 12067140. PMID 40365400.
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