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The Current Status of Drug Discovery for the Oxytocin Receptor

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Oxytocin

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2384))

Abstract

The oxytocin receptor plays a significant role in peripheral regulation of parturition and lactation. Given this important role, multiple drug discovery programs have been conducted to develop agonists and antagonists for peripheral activity. The role of the oxytocin receptor in the central nervous system is also significant, promoting social interaction, trust, and empathy in humans. As such, molecules that can access the central nervous system and target the oxytocin receptor are of significant interest. Due to the role of the oxytocin receptor in regulating social function and psychological well-being, agonists of this receptor have considerable promise for the treatment of numerous neuropsychiatric conditions. The poor pharmacokinetic properties and blood–brain barrier penetration of peptide-based molecules means nonpeptide compounds have more commonly been the focus for central nervous system activity. This chapter aims to summarize the current standing of peptide and nonpeptide drug discovery for antagonists and agonists of the oxytocin receptor and focusses on centrally active nonpeptidic agonists.

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References

  1. Jones DE, Greenberg M, Crowley M (2015) Early social-emotional functioning and public health: the relationship between kindergarten social competence and future wellness. Am J Public Health 105(11):2283–2290. https://doi.org/10.2105/AJPH.2015.302630

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dutescu MM, Popescu RE, Balcu L, Duica LC, Strunoiu LM, Alexandru DO, Pirlog MC (2018) Social functioning in schizophrenia clinical correlations. Curr Health Sci J 44(2):151–156. https://doi.org/10.12865/CHSJ.44.02.10

    Article  PubMed  PubMed Central  Google Scholar 

  3. Fett AK, Shergill SS, Krabbendam L (2015) Social neuroscience in psychiatry: unravelling the neural mechanisms of social dysfunction. Psychol Med 45(6):1145–1165. https://doi.org/10.1017/S0033291714002487

    Article  CAS  PubMed  Google Scholar 

  4. Hecht H, von Zerssen D, Krieg C, Possl J, Wittchen HU (1989) Anxiety and depression: comorbidity, psychopathology, and social functioning. Compr Psychiatry 30(5):420–433. https://doi.org/10.1016/0010-440x(89)90008-4

    Article  CAS  PubMed  Google Scholar 

  5. Kupferberg A, Bicks L, Hasler G (2016) Social functioning in major depressive disorder. Neurosci Biobehav Rev 69:313–332. https://doi.org/10.1016/j.neubiorev.2016.07.002

    Article  PubMed  Google Scholar 

  6. WHO (2011) Global status report on non-communicable diseases. WHO, Geneva

    Google Scholar 

  7. Murray ML, Hsia Y, Glaser K, Simonoff E, Murphy DG, Asherson PJ, Eklund H, Wong IC (2014) Pharmacological treatments prescribed to people with autism spectrum disorder (ASD) in primary health care. Psychopharmacology 231(6):1011–1021. https://doi.org/10.1007/s00213-013-3140-7

    Article  CAS  PubMed  Google Scholar 

  8. Serretti A, Kato M (2008) The serotonin transporter gene and effectiveness of SSRIs. Expert Rev Neurother 8(1):111–120. https://doi.org/10.1586/14737175.8.1.111

    Article  PubMed  Google Scholar 

  9. Cascade E, Kalali AH, Kennedy SH (2009) Real-world data on SSRI antidepressant side effects. Psychiatry (Edgmont) 6(2):16–18

    Google Scholar 

  10. Griebel G, Holsboer F (2012) Neuropeptide receptor ligands as drugs for psychiatric diseases: the end of the beginning? Nat Rev Drug Discov 11(6):462–478. https://doi.org/10.1038/nrd3702

    Article  CAS  PubMed  Google Scholar 

  11. Gimpl G, Fahrenholz F (2001) The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81(2):629–683. https://doi.org/10.1152/physrev.2001.81.2.629

    Article  CAS  PubMed  Google Scholar 

  12. Manning M, Misicka A, Olma A, Bankowski K, Stoev S, Chini B, Durroux T, Mouillac B, Corbani M, Guillon G (2012) Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J Neuroendocrinol 24(4):609–628. https://doi.org/10.1111/j.1365-2826.2012.02303.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rinne M, Tanoli ZU, Khan A, Xhaard H (2019) Cartography of rhodopsin-like G protein-coupled receptors across vertebrate genomes. Sci Rep 9(1):7058. https://doi.org/10.1038/s41598-018-33120-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Baribeau D, Anagnostou E (2015) Oxytocin and vasopressin: linking pituitary neuropeptides and their receptors to social neurocircuits. Front Neurosci 9(335). https://doi.org/10.3389/fnins.2015.00335

  15. Chini B, Mouillac B, Ala Y, Balestre MN, Trumpp-Kallmeyer S, Hoflack J, Elands J, Hibert M, Manning M, Jard S et al (1995) Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor. EMBO J 14(10):2176–2182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Frantz MC, Pellissier LP, Pflimlin E, Loison S, Gandia J, Marsol C, Durroux T, Mouillac B, Becker JAJ, Le Merrer J, Valencia C, Villa P, Bonnet D, Hibert M (2018) LIT-001, the first nonpeptide oxytocin receptor agonist that improves social interaction in a mouse model of autism. J Med Chem 61(19):8670–8692. https://doi.org/10.1021/acs.jmedchem.8b00697

    Article  CAS  PubMed  Google Scholar 

  17. Busnelli M, Bulgheroni E, Manning M, Kleinau G, Chini B (2013) Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors. J Pharmacol Exp Ther 346(2):318–327. https://doi.org/10.1124/jpet.113.202994

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Makita N, Sato T, Yajima-Shoji Y, Sato J, Manaka K, Eda-Hashimoto M, Ootaki M, Matsumoto N, Nangaku M, Iiri T (2016) Analysis of the V2 vasopressin receptor (V2R) mutations causing partial nephrogenic diabetes insipidus highlights a sustainable signaling by a non-peptide V2R agonist. J Biol Chem 291(43):22460–22471. https://doi.org/10.1074/jbc.M116.733220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sawyer WH (1977) Evolution of neurohypophyseal hormones and their receptors. Fed Proc 36(6):1842–1847

    CAS  PubMed  Google Scholar 

  20. Murphy MR, Seckl JR, Burton S, Checkley SA, Lightman SL (1987) Changes in oxytocin and vasopressin secretion during sexual activity in men. J Clin Endocrinol Metab 65(4):738–741. https://doi.org/10.1210/jcem-65-4-738

    Article  CAS  PubMed  Google Scholar 

  21. Li C, Wang W, Summer SN, Westfall TD, Brooks DP, Falk S, Schrier RW (2008) Molecular mechanisms of antidiuretic effect of oxytocin. J Am Soc Nephrol 19(2):225–232. https://doi.org/10.1681/ASN.2007010029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hicks C, Ramos L, Reekie T, Misagh GH, Narlawar R, Kassiou M, McGregor IS (2014) Body temperature and cardiac changes induced by peripherally administered oxytocin, vasopressin and the non-peptide oxytocin receptor agonist WAY 267,464: a biotelemetry study in rats. Br J Pharmacol 171(11):2868–2887. https://doi.org/10.1111/bph.12613

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jurek B, Neumann ID (2018) The oxytocin receptor: from intracellular signaling to behavior. Physiol Rev 98(3):1805–1908. https://doi.org/10.1152/physrev.00031.2017

    Article  CAS  PubMed  Google Scholar 

  24. Higashida H, Yokoyama S, Huang J-J, Liu L, Ma W-J, Akther S, Higashida C, Kikuchi M, Minabe Y, Munesue T (2012) Social memory, amnesia, and autism: brain oxytocin secretion is regulated by NAD+ metabolites and single nucleotide polymorphisms of CD38. Neurochem Int 61(6):828–838. https://doi.org/10.1016/j.neuint.2012.01.030

    Article  CAS  PubMed  Google Scholar 

  25. Israel S, Lerer E, Shalev I, Uzefovsky F, Riebold M, Laiba E, Bachner-Melman R, Maril A, Bornstein G, Knafo A, Ebstein RP (2009) The oxytocin receptor (OXTR) contributes to prosocial fund allocations in the dictator game and the social value orientations task. PLoS One 4(5):e5535. https://doi.org/10.1371/journal.pone.0005535

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kogan A, Saslow LR, Impett EA, Oveis C, Keltner D, Rodrigues Saturn S (2011) Thin-slicing study of the oxytocin receptor (OXTR) gene and the evaluation and expression of the prosocial disposition. Proc Natl Acad Sci U S A 108(48):19189. https://doi.org/10.1073/pnas.1112658108

    Article  PubMed  PubMed Central  Google Scholar 

  27. Tost H, Kolachana B, Hakimi S, Lemaitre H, Verchinski BA, Mattay VS, Weinberger DR, Meyer-Lindenberg A (2010) A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function. Proc Natl Acad Sci U S A 107(31):13936. https://doi.org/10.1073/pnas.1003296107

    Article  PubMed  PubMed Central  Google Scholar 

  28. Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D (2009) Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proc Natl Acad Sci U S A 106(50):21437. https://doi.org/10.1073/pnas.0909579106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chen FS, Kumsta R, von Dawans B, Monakhov M, Ebstein RP, Heinrichs M (2011) Common oxytocin receptor gene (OXTR) polymorphism and social support interact to reduce stress in humans. Proc Natl Acad Sci U S A 108(50):19937. https://doi.org/10.1073/pnas.1113079108

    Article  PubMed  PubMed Central  Google Scholar 

  30. Williams JR, Insel TR, Harbaugh CR, Carter CS (1994) Oxytocin administered centrally facilitates formation of a partner preference in female prairie voles (Microtus ochrogaster). J Neuroendocrinol 6(3):247–250. https://doi.org/10.1111/j.1365-2826.1994.tb00579.x

    Article  CAS  PubMed  Google Scholar 

  31. Keebaugh AC, Barrett CE, Laprairie JL, Jenkins JJ, Young LJ (2015) RNAi knockdown of oxytocin receptor in the nucleus accumbens inhibits social attachment and parental care in monogamous female prairie voles. Soc Neurosci 10(5):561–570. https://doi.org/10.1080/17470919.2015.1040893

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gordon I, Zagoory-Sharon O, Leckman JF, Feldman R (2010) Oxytocin and the development of parenting in humans. Biol Psychiatry 68(4):377–382. https://doi.org/10.1016/j.biopsych.2010.02.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Walum H, Lichtenstein P, Neiderhiser JM, Reiss D, Ganiban JM, Spotts EL, Pedersen NL, Anckarsater H, Larsson H, Westberg L (2012) Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior. Biol Psychiatry 71(5):419–426. https://doi.org/10.1016/j.biopsych.2011.09.002

    Article  CAS  PubMed  Google Scholar 

  34. Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E (2005) Oxytocin increases trust in humans. Nature 435(7042):673–676. https://doi.org/10.1038/nature03701

    Article  CAS  PubMed  Google Scholar 

  35. Shahrestani S, Kemp AH, Guastella AJ (2013) The impact of a single administration of intranasal oxytocin on the recognition of basic emotions in humans: a meta-analysis. Neuropsychopharmacology 38(10):1929–1936. https://doi.org/10.1038/npp.2013.86

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hurlemann R, Patin A, Onur OA, Cohen MX, Baumgartner T, Metzler S, Dziobek I, Gallinat J, Wagner M, Maier W, Kendrick KM (2010) Oxytocin enhances amygdala-dependent, socially reinforced learning and emotional empathy in humans. J Neurosci 30(14):4999–5007. https://doi.org/10.1523/JNEUROSCI.5538-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Young LJ, Barrett CE (2015) Can oxytocin treat autism? Science 347(6224):825. https://doi.org/10.1126/science.aaa8120

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. De Dreu CKW, Greer LL, Handgraaf MJJ, Shalvi S, Van Kleef GA, Baas M, Ten Velden FS, Van Dijk E, Feith SWW (2010) The neuropeptide oxytocin regulates parochial altruism in intergroup conflict among humans. Science 328(5984):1408. https://doi.org/10.1126/science.1189047

    Article  CAS  PubMed  Google Scholar 

  39. De Dreu CKW, Greer LL, Van Kleef GA, Shalvi S, Handgraaf MJJ (2011) Oxytocin promotes human ethnocentrism. Proc Natl Acad Sci U S A 108(4):1262. https://doi.org/10.1073/pnas.1015316108

    Article  PubMed  PubMed Central  Google Scholar 

  40. Shamay-Tsoory SG, Fischer M, Dvash J, Harari H, Perach-Bloom N, Levkovitz Y (2009) Intranasal administration of oxytocin increases envy and schadenfreude (gloating). Biol Psychiatry 66(9):864–870. https://doi.org/10.1016/j.biopsych.2009.06.009

    Article  CAS  PubMed  Google Scholar 

  41. Beery AK (2015) Antisocial oxytocin: complex effects on social behavior. Curr Opin Behav Sci 6:174–182. https://doi.org/10.1016/j.cobeha.2015.11.006

    Article  Google Scholar 

  42. Cochran DM, Fallon D, Hill M, Frazier JA (2013) The role of oxytocin in psychiatric disorders: a review of biological and therapeutic research findings. Harv Rev Psychiatry 21(5):219–247. https://doi.org/10.1097/HRP.0b013e3182a75b7d

    Article  PubMed  PubMed Central  Google Scholar 

  43. Goodin BR, Ness TJ, Robbins MT (2015) Oxytocin – a multifunctional analgesic for chronic deep tissue pain. Curr Pharm Des 21(7):906–913. https://doi.org/10.2174/1381612820666141027111843

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Macdonald K, Feifel D (2012) Oxytocin in schizophrenia: a review of evidence for its therapeutic effects. Acta Neuropsychiatr 24(3):130–146. https://doi.org/10.1111/j.1601-5215.2011.00634.x

    Article  PubMed  Google Scholar 

  45. Macdonald K, Macdonald TM (2010) The peptide that binds: a systematic review of oxytocin and its prosocial effects in humans. Harv Rev Psychiatry 18(1):1–21. https://doi.org/10.3109/10673220903523615

    Article  PubMed  Google Scholar 

  46. Modi ME, Young LJ (2012) The oxytocin system in drug discovery for autism: animal models and novel therapeutic strategies. Horm Behav 61(3):340–350. https://doi.org/10.1016/j.yhbeh.2011.12.010

    Article  CAS  PubMed  Google Scholar 

  47. Guastella AJ, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ, Hickie IB (2010) Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 67(7):692–694. https://doi.org/10.1016/j.biopsych.2009.09.020

    Article  CAS  PubMed  Google Scholar 

  48. Hollander E, Bartz J, Chaplin W, Phillips A, Sumner J, Soorya L, Anagnostou E, Wasserman S (2007) Oxytocin increases retention of social cognition in autism. Biol Psychiatry 61(4):498–503. https://doi.org/10.1016/j.biopsych.2006.05.030

    Article  CAS  PubMed  Google Scholar 

  49. Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, Sirigu A (2010) Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci U S A 107(9):4389–4394. https://doi.org/10.1073/pnas.0910249107

    Article  PubMed  PubMed Central  Google Scholar 

  50. Hall SS, Lightbody AA, McCarthy BE, Parker KJ, Reiss AL (2012) Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome. Psychoneuroendocrinology 37(4):509–518. https://doi.org/10.1016/j.psyneuen.2011.07.020

    Article  CAS  PubMed  Google Scholar 

  51. Hollander E, Novotny S, Hanratty M, Yaffe R, DeCaria CM, Aronowitz BR, Mosovich S (2003) Oxytocin infusion reduces repetitive behaviors in adults with autistic and Asperger’s disorders. Neuropsychopharmacology 28(1):193–198. https://doi.org/10.1038/sj.npp.1300021

    Article  CAS  PubMed  Google Scholar 

  52. Lee MR, Weerts EM (2016) Oxytocin for the treatment of drug and alcohol use disorders. Behav Pharmacol 27(8):640–648. https://doi.org/10.1097/FBP.0000000000000258

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Neumann ID, Landgraf R (2012) Balance of brain oxytocin and vasopressin: implications for anxiety, depression, and social behaviors. Trends Neurosci 35(11):649–659. https://doi.org/10.1016/j.tins.2012.08.004

    Article  CAS  PubMed  Google Scholar 

  54. Leng G, Ludwig M (2016) Intranasal oxytocin: myths and delusions. Biol Psychiatry 79(3):243–250. https://doi.org/10.1016/j.biopsych.2015.05.003

    Article  CAS  PubMed  Google Scholar 

  55. Renukuntla J, Vadlapudi AD, Patel A, Boddu SH, Mitra AK (2013) Approaches for enhancing oral bioavailability of peptides and proteins. Int J Pharm 447(1–2):75–93. https://doi.org/10.1016/j.ijpharm.2013.02.030

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dale HH (1906) On some physiological actions of ergot. J Physiol 34(3):163–206. https://doi.org/10.1113/jphysiol.1906.sp001148

    Article  PubMed  PubMed Central  Google Scholar 

  57. Russell JA, Leng G (1998) Sex, parturition and motherhood without oxytocin? J Endocrinol 157(3):343–359. https://doi.org/10.1677/joe.0.1570343

    Article  CAS  PubMed  Google Scholar 

  58. Douglas AJ, Leng G, Russell JA (2002) The importance of oxytocin mechanisms in the control of mouse parturition. Reproduction 123(4):543–552. https://doi.org/10.1530/rep.0.1230543

    Article  CAS  PubMed  Google Scholar 

  59. Crowley WR, Armstrong WE (1992) Neurochemical regulation of oxytocin secretion in lactation. Endocr Rev 13(1):33–65. https://doi.org/10.1210/edrv-13-1-33

    Article  CAS  PubMed  Google Scholar 

  60. Tyzio R, Cossart R, Khalilov I, Minlebaev M, HĂĽbner CA, Represa A, Ben-Ari Y, Khazipov R (2006) Maternal oxytocin triggers a transient inhibitory switch in GABA signaling in the fetal brain during delivery. Science 314(5806):1788. https://doi.org/10.1126/science.1133212

    Article  CAS  PubMed  Google Scholar 

  61. Thackare H, Nicholson HD, Whittington K (2006) Oxytocin—its role in male reproduction and new potential therapeutic uses. Hum Reprod Update 12(4):437–448. https://doi.org/10.1093/humupd/dmk002

    Article  CAS  PubMed  Google Scholar 

  62. Atasoy D, Betley JN, Su HH, Sternson SM (2012) Deconstruction of a neural circuit for hunger. Nature 488(7410):172–177. https://doi.org/10.1038/nature11270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Gulliver D, Werry E, Reekie TA, Katte TA, Jorgensen W, Kassiou M (2019) Targeting the oxytocin system: new pharmacotherapeutic approaches. Trends Pharmacol Sci 40(1):22–37. https://doi.org/10.1016/j.tips.2018.11.001

    Article  CAS  PubMed  Google Scholar 

  64. Caldwell HK, Lee HJ, Macbeth AH, Young WS 3rd (2008) Vasopressin: behavioral roles of an “original” neuropeptide. Prog Neurobiol 84(1):1–24. https://doi.org/10.1016/j.pneurobio.2007.10.007

    Article  CAS  PubMed  Google Scholar 

  65. Budden A, Chen LJY, Henry A (2014) High-dose versus low-dose oxytocin infusion regimens for induction of labour at term. Cochrane Database Syst Rev (10). https://doi.org/10.1002/14651858.CD009701.pub2

  66. Widmer M, Piaggio G, Nguyen TMH, Osoti A, Owa OO, Misra S, Coomarasamy A, Abdel-Aleem H, Mallapur AA, Qureshi Z, Lumbiganon P, Patel AB, Carroli G, Fawole B, Goudar SS, Pujar YV, Neilson J, Hofmeyr GJ, Su LL, Ferreira de Carvalho J, Pandey U, Mugerwa K, Shiragur SS, Byamugisha J, Giordano D, Gülmezoglu AM (2018) Heat-stable carbetocin versus oxytocin to prevent hemorrhage after vaginal birth. N Engl J Med 379(8):743–752. https://doi.org/10.1056/NEJMoa1805489

    Article  CAS  PubMed  Google Scholar 

  67. Åkerlund M, Carlsson AM, Melin P, Trojnar J (1985) The effect on the human uterus of two newly developed competitive inhibitors of oxytocin and vasopressin. Acta Obstet Gynecol Scand 64(6):499–504. https://doi.org/10.3109/00016348509156728

    Article  PubMed  Google Scholar 

  68. Lamont RF, Kam KYR (2008) Atosiban as a tocolytic for the treatment of spontaneous preterm labor. Expert Rev Obstet Gynecol 3(2):163–174. https://doi.org/10.1586/17474108.3.2.163

    Article  CAS  Google Scholar 

  69. Wiśniewski K (2019) Design of oxytocin analogs. In: Goetz G (ed) Cyclic peptide design, Methods in molecular biology, vol 2001. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-9504-2_11

    Chapter  Google Scholar 

  70. Katte TA, Kassiou M (2017) A patent review of oxytocin receptor antagonists 2013–2017. Expert Opin Ther Pat 27(12):1287–1290. https://doi.org/10.1080/13543776.2017.1379992

    Article  CAS  PubMed  Google Scholar 

  71. Muttenthaler M, Andersson A, Vetter I, Menon R, Busnelli M, Ragnarsson L, Bergmayr C, Arrowsmith S, Deuis JR, Chiu HS, Palpant NJ, O’Brien M, Smith TJ, Wray S, Neumann ID, Gruber CW, Lewis RJ, Alewood PF (2017) Subtle modifications to oxytocin produce ligands that retain potency and improved selectivity across species. Sci Signal 10(508). https://doi.org/10.1126/scisignal.aan3398

  72. Beard R, Stucki A, Schmitt M, Py G, Grundschober C, Gee AD, Tate EW (2018) Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs. Bioorg Med Chem 26(11):3039–3045. https://doi.org/10.1016/j.bmc.2018.03.019

    Article  CAS  PubMed  Google Scholar 

  73. Wiśniewski K, Alagarsamy S, Galyean R, Tariga H, Thompson D, Ly B, Wiśniewska H, Qi S, Croston G, Laporte R, Rivière PJM, Schteingart CD (2014) New, potent, and selective peptidic oxytocin receptor agonists. J Med Chem 57(12):5306–5317. https://doi.org/10.1021/jm500365s

    Article  CAS  PubMed  Google Scholar 

  74. Kablaoui N, Vanase-Frawley M, Sciabola S (2018) Hybrid peptide-small molecule oxytocin analogs are potent and selective agonists of the oxytocin receptor. Bioorg Med Chem Lett 28(3):415–419. https://doi.org/10.1016/j.bmcl.2017.12.027

    Article  CAS  PubMed  Google Scholar 

  75. Vrachnis N, Malamas FM, Sifakis S, Deligeoroglou E, Iliodromiti Z (2011) The oxytocin-oxytocin receptor system and its antagonists as tocolytic agents. Int J Endocrinol 2011:350546. https://doi.org/10.1155/2011/350546

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Bouvier M (2001) Oligomerization of G-protein-coupled transmitter receptors. Nat Rev Neurosci 2(4):274–286. https://doi.org/10.1038/35067575

    Article  CAS  PubMed  Google Scholar 

  77. Busnelli M, Kleinau G, Muttenthaler M, Stoev S, Manning M, Bibic L, Howell LA, McCormick PJ, Di Lascio S, Braida D, Sala M, Rovati GE, Bellini T, Chini B (2016) Design and characterization of superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure. J Med Chem 59(15):7152–7166. https://doi.org/10.1021/acs.jmedchem.6b00564

    Article  CAS  PubMed  Google Scholar 

  78. Ermisch A, Ruhle HJ, Landgraf R, Hess J (1985) Blood-brain barrier and peptides. J Cereb Blood Flow Metab 5(3):350–357. https://doi.org/10.1038/jcbfm.1985.49

    Article  CAS  PubMed  Google Scholar 

  79. Humphrey MJ, Ringrose PS (1986) Peptides and related drugs: a review of their absorption, metabolism, and excretion. Drug Metab Rev 17(3–4):283–310. https://doi.org/10.3109/03602538608998293

    Article  CAS  PubMed  Google Scholar 

  80. Pitt GR, Batt AR, Haigh RM, Penson AM, Robson PA, Rooker DP, Tartar AL, Trim JE, Yea CM, Roe MB (2004) Non-peptide oxytocin agonists. Bioorg Med Chem Lett 14(17):4585–4589. https://doi.org/10.1016/j.bmcl.2004.04.107

    Article  CAS  PubMed  Google Scholar 

  81. Williams PD, Anderson PS, Ball RG, Bock MG, Carroll L, Chiu S-HL, Clineschmidt BV, Culberson JC, Erb JM (1994) 1-(((7,7-Dimethyl-2(S)-(2(S)-amino-4-(methylsulfonyl)butyramido)bicyclo[2.2.1]heptan-1(S)-yl)methyl)sulfonyl)-4-(2-methylphenyl)piperazine (L-368,899): an orally bioavailable, non-peptide oxytocin antagonist with potential utility for managing preterm labor. J Med Chem 37(5):565–571. https://doi.org/10.1021/jm00031a004

    Article  CAS  PubMed  Google Scholar 

  82. Williams PD, Clineschmidt BV, Erb JM, Freidinger RM, Guidotti MT, Lis EV, Pawluczyk JM, Pettibone DJ, Reiss DR (1995) 1-[1-[4-[(N-Acetyl-4-piperidinyl)oxy]-2- methoxybenzoyl]piperidin-4-yl]-4H-3,1- benzoxazin-2(1H)-one (L-371,257): a new, orally bioavailable, non-peptide oxytocin antagonist. J Med Chem 38(23):4634–4636. https://doi.org/10.1021/jm00023a002

    Article  CAS  PubMed  Google Scholar 

  83. Smith AL, Walum H, Connor-Stroud F, Freeman SM, Inoue K, Parr LA, Goodman MM, Young LJ (2017) An evaluation of central penetration from a peripherally administered oxytocin receptor selective antagonist in nonhuman primates. Bioorg Med Chem 25(1):305–315. https://doi.org/10.1016/j.bmc.2016.10.035

    Article  CAS  PubMed  Google Scholar 

  84. Borthwick AD, Liddle J, Davies DE, Exall AM, Hamlett C, Hickey DM, Mason AM, Smith IED, Nerozzi F, Peace S, Pollard D, Sollis SL, Allen MJ, Woollard PM, Pullen MA, Westfall TD, Stanislaus DJ (2012) Pyridyl-2,5-diketopiperazines as potent, selective, and orally bioavailable oxytocin antagonists: synthesis, pharmacokinetics, and in vivo potency. J Med Chem 55(2):783–796. https://doi.org/10.1021/jm201287w

    Article  CAS  PubMed  Google Scholar 

  85. Mahar KM, Stier B, Fries M, McCallum SW (2015) A single- and multiple-dose study to investigate the pharmacokinetics of epelsiban and its metabolite, GSK2395448, in healthy female volunteers. Clin Pharmacol Drug Dev 4(6):418–426. https://doi.org/10.1002/cpdd.210

    Article  CAS  PubMed  Google Scholar 

  86. https://www.obseva.com/nolasiban/ (2019) Nolasiban (OBE001) —Assisted Reproductive Technology

  87. Liddle J, Allen MJ, Borthwick AD, Brooks DP, Davies DE, Edwards RM, Exall AM, Hamlett C, Irving WR, Mason AM, McCafferty GP, Nerozzi F, Peace S, Philp J, Pollard D, Pullen MA, Shabbir SS, Sollis SL, Westfall TD, Woollard PM, Wu C, Hickey DMB (2008) The discovery of GSK221149A: a potent and selective oxytocin antagonist. Bioorg Med Chem Lett 18(1):90–94. https://doi.org/10.1016/j.bmcl.2007.11.008

    Article  CAS  PubMed  Google Scholar 

  88. Brown A, Brown TB, Calabrese A, Ellis D, Puhalo N, Ralph M, Watson L (2010) Triazole oxytocin antagonists: identification of an aryloxyazetidine replacement for a biaryl substituent. Bioorg Med Chem Lett 20(2):516–520. https://doi.org/10.1016/j.bmcl.2009.11.097

    Article  CAS  PubMed  Google Scholar 

  89. Busnelli M, Saulière A, Manning M, Bouvier M, Galés C, Chini B (2012) Functional selective oxytocin-derived agonists discriminate between individual G protein family subtypes. J Biol Chem 287(6):3617–3629

    Article  CAS  PubMed  Google Scholar 

  90. Chollet A (2015) Pyrrolidine derivatives as oxytocin/vasopressin V1A receptors antagonists. United States Patent

    Google Scholar 

  91. McCafferty GP, Pullen MA, Wu C, Edwards RM, Allen MJ, Woollard PM, Borthwick AD, Liddle J, Hickey DMB, Brooks DP, Westfall TD (2007) Use of a novel and highly selective oxytocin receptor antagonist to characterize uterine contractions in the rat. Am J Phys Regul Integr Comp Phys 293(1):R299–R305. https://doi.org/10.1152/ajpregu.00057.2007

    Article  CAS  Google Scholar 

  92. 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. Prog Brain Res 170:473–512. https://doi.org/10.1016/S0079-6123(08)00437-8

    Article  CAS  PubMed  Google Scholar 

  93. Moy SS, Teng BL, Nikolova VD, Riddick NV, Simpson CD, Van Deusen A, Janzen WP, Sassano MF, Pedersen CA, Jarstfer MB (2019) Prosocial effects of an oxytocin metabolite, but not synthetic oxytocin receptor agonists, in a mouse model of autism. Neuropharmacology 144:301–311. https://doi.org/10.1016/j.neuropharm.2018.10.036

    Article  CAS  PubMed  Google Scholar 

  94. Frantz MC, Rodrigo J, Boudier L, Durroux T, Mouillac B, Hibert M (2010) Subtlety of the structure-affinity and structure-efficacy relationships around a nonpeptide oxytocin receptor agonist. J Med Chem 53(4):1546–1562. https://doi.org/10.1021/jm901084f

    Article  CAS  PubMed  Google Scholar 

  95. Hudson P, Pitt GRW, Batt AR, Roe MB (2004) Piperazines as oxytocin agonists. United States Patent

    Google Scholar 

  96. Ring RH, Schechter LE, Leonard SK, Dwyer JM, Platt BJ, Graf R, Grauer S, Pulicicchio C, Resnick L, Rahman Z, Sukoff Rizzo SJ, Luo B, Beyer CE, Logue SF, Marquis KL, Hughes ZA, Rosenzweig-Lipson S (2010) Receptor and behavioral pharmacology of WAY-267464, a non-peptide oxytocin receptor agonist. Neuropharmacology 58(1):69–77. https://doi.org/10.1016/j.neuropharm.2009.07.016

    Article  CAS  PubMed  Google Scholar 

  97. Hicks C, Jorgensen W, Brown C, Fardell J, Koehbach J, Gruber CW, Kassiou M, Hunt GE, McGregor IS (2012) The nonpeptide oxytocin receptor agonist WAY 267,464: receptor-binding profile, prosocial effects and distribution of c-Fos expression in adolescent rats. J Neuroendocrinol 24(7):1012–1029. https://doi.org/10.1111/j.1365-2826.2012.02311.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Jorgensen WT, Gulliver DW, Werry EL, Reekie T, Connor M, Kassiou M (2016) Flexible analogues of WAY-267,464: synthesis and pharmacology at the human oxytocin and vasopressin 1a receptors. Eur J Med Chem 108:730–740. https://doi.org/10.1016/j.ejmech.2015.11.050

    Article  CAS  PubMed  Google Scholar 

  99. Carter CS (2017) The oxytocin-vasopressin pathway in the context of love and fear. Front Endocrinol (Lausanne) 8:356. https://doi.org/10.3389/fendo.2017.00356

    Article  Google Scholar 

  100. Hicks C, Ramos L, Reekie TA, Narlawar R, Kassiou M, McGregor IS (2015) WAY 267,464, a non-peptide oxytocin receptor agonist, impairs social recognition memory in rats through a vasopressin 1A receptor antagonist action. Psychopharmacology 232(15):2659–2667. https://doi.org/10.1007/s00213-015-3902-5

    Article  CAS  PubMed  Google Scholar 

  101. Jorgensen WT, Gulliver DW, Katte TA, Werry EL, Reekie TA, Connor M, Kassiou M (2018) Conformationally rigid derivatives of WAY-267,464: synthesis and pharmacology at the human oxytocin and vasopressin-1a receptors. Eur J Med Chem 143:1644–1656. https://doi.org/10.1016/j.ejmech.2017.10.059

    Article  CAS  PubMed  Google Scholar 

  102. Kassiou M, Jorgensen W, Werry E, Reekie T, Bowen M, McGregor IS (2018) Non-peptide oxytocin receptor agonists. Australia Patent

    Google Scholar 

  103. Passoni I, Leonzino M, Gigliucci V, Chini B, Busnelli M (2016) Carbetocin is a functional selective Gq agonist that does not promote oxytocin receptor recycling after inducing β-arrestin-independent internalisation. J Neuroendocrinol 28(4). https://doi.org/10.1111/jne.12363

  104. Tachibana M, Kagitani-Shimono K, Mohri I, Yamamoto T, Sanefuji W, Nakamura A, Oishi M, Kimura T, Onaka T, Ozono K, Taniike M (2013) Long-term administration of intranasal oxytocin is a safe and promising therapy for early adolescent boys with autism spectrum disorders. J Child Adolesc Psychopharmacol 23(2):123–127. https://doi.org/10.1089/cap.2012.0048

    Article  CAS  PubMed  Google Scholar 

  105. Hilfiger L, Zhao Q, Kerspern D, Inquimbert P, Andry V, Goumon Y, Darbon P, Hibert M, Charlet A (2020) A nonpeptide oxytocin receptor agonist for a durable relief of inflammatory pain. Sci Rep 10(1):3017. https://doi.org/10.1038/s41598-020-59929-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Waltenspühl Y, Schöppe J, Ehrenmann J, Kummer L, Plückthun A (2020) Crystal structure of the human oxytocin receptor. Sci Adv 6(29):eabb5419. https://doi.org/10.1126/sciadv.abb5419

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Nashar, P.E., Whitfield, A.A., Mikusek, J., Reekie, T.A. (2022). The Current Status of Drug Discovery for the Oxytocin Receptor . In: Werry, E.L., Reekie, T.A., Kassiou, M. (eds) Oxytocin. Methods in Molecular Biology, vol 2384. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1759-5_10

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