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Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
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Melatonin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Melatonin Receptors [6]) are activated by the endogenous ligands melatonin and clinically used drugs like ramelteon, agomelatine and tasimelteon.
MT1 receptor C Show summary »« Hide summary More detailed page
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MT2 receptor C Show summary »« Hide summary More detailed page
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* Key recommended reading is highlighted with an asterisk
* Boutin JA, Witt-Enderby PA, Sotriffer C, Zlotos DP. (2020) Melatonin receptor ligands: A pharmaco-chemical perspective. J Pineal Res, 69 (3): e12672. [PMID:32531076]
* Cecon E, Oishi A, Jockers R. (2018) Melatonin receptors: molecular pharmacology and signalling in the context of system bias. Br J Pharmacol, 175 (16): 3263-3280. [PMID:28707298]
* Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. (2010) International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev, 62 (3): 343-80. [PMID:20605968]
* Jockers R, Delagrange P, Dubocovich ML, Markus RP, Renault N, Tosini G, Cecon E, Zlotos DP. (2016) Update on melatonin receptors: IUPHAR Review 20. Br J Pharmacol, 173 (18): 2702-25. [PMID:27314810]
* Karamitri A, Jockers R. (2019) Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol, 15 (2): 105-125. [PMID:30531911]
* Liu J, Clough SJ, Hutchinson AJ, Adamah-Biassi EB, Popovska-Gorevski M, Dubocovich ML. (2016) MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annu Rev Pharmacol Toxicol, 56: 361-83. [PMID:26514204]
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6. Dubocovich ML, Delagrange P, Krause DN, Sugden D, Cardinali DP, Olcese J. (2010) International Union of Basic and Clinical Pharmacology. LXXV. Nomenclature, classification, and pharmacology of G protein-coupled melatonin receptors. Pharmacol Rev, 62 (3): 343-80. [PMID:20605968]
7. Dubocovich ML, Masana MI, Iacob S, Sauri DM. (1997) Melatonin receptor antagonists that differentiate between the human Mel1a and Mel1b recombinant subtypes are used to assess the pharmacological profile of the rabbit retina ML1 presynaptic heteroreceptor. Naunyn Schmiedebergs Arch Pharmacol, 355 (3): 365-75. [PMID:9089668]
8. Dubocovich ML, Yun K, Al-Ghoul WM, Benloucif S, Masana MI. (1998) Selective MT2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J, 12 (12): 1211-20. [PMID:9737724]
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12. Huete-Toral F, Crooke A, Martínez-Águila A, Pintor J. (2015) Melatonin receptors trigger cAMP production and inhibit chloride movements in nonpigmented ciliary epithelial cells. J Pharmacol Exp Ther, 352 (1): 119-28. [PMID:25344385]
13. Karamitri A, Jockers R. (2019) Melatonin in type 2 diabetes mellitus and obesity. Nat Rev Endocrinol, 15 (2): 105-125. [PMID:30531911]
14. Kato K, Hirai K, Nishiyama K, Uchikawa O, Fukatsu K, Ohkawa S, Kawamata Y, Hinuma S, Miyamoto M. (2005) Neurochemical properties of ramelteon (TAK-375), a selective MT1/MT2 receptor agonist. Neuropharmacology, 48 (2): 301-10. [PMID:15695169]
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16. Lucchelli A, Santagostino-Barbone MG, Tonini M. (1997) Investigation into the contractile response of melatonin in the guinea-pig isolated proximal colon: the role of 5-HT4 and melatonin receptors. Br J Pharmacol, 121 (8): 1775-81. [PMID:9283717]
17. Molinari EJ, North PC, Dubocovich ML. (1996) 2-[125I]iodo-5-methoxycarbonylamino-N-acetyltryptamine: a selective radioligand for the characterization of melatonin ML2 binding sites. Eur J Pharmacol, 301 (1-3): 159-68. [PMID:8773460]
18. Nosjean O, Ferro M, Coge F, Beauverger P, Henlin JM, Lefoulon F, Fauchere JL, Delagrange P, Canet E, Boutin JA. (2000) Identification of the melatonin-binding site MT3 as the quinone reductase 2. J Biol Chem, 275 (40): 31311-7. [PMID:10913150]
19. Nosjean O, Nicolas JP, Klupsch F, Delagrange P, Canet E, Boutin JA. (2001) Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2 . Biochem Pharmacol, 61 (11): 1369-79. [PMID:11331072]
20. Popova JS, Dubocovich ML. (1995) Melatonin receptor-mediated stimulation of phosphoinositide breakdown in chick brain slices. J Neurochem, 64 (1): 130-8. [PMID:7798906]
21. Rajaratnam SM, Polymeropoulos MH, Fisher DM, Roth T, Scott C, Birznieks G, Klerman EB. (2009) Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet, 373 (9662): 482-91. [PMID:19054552]
22. Rawashdeh O, Hudson RL, Stepien I, Dubocovich ML. (2011) Circadian periods of sensitivity for ramelteon on the onset of running-wheel activity and the peak of suprachiasmatic nucleus neuronal firing rhythms in C3H/HeN mice. Chronobiol Int, 28 (1): 31-8. [PMID:21182402]
23. Spadoni G, Bedini A, Lucarini S, Mari M, Caignard DH, Boutin JA, Delagrange P, Lucini V, Scaglione F, Lodola A et al.. (2015) Highly Potent and Selective MT2 Melatonin Receptor Full Agonists from Conformational Analysis of 1-Benzyl-2-acylaminomethyl-tetrahydroquinolines. J Med Chem, 58 (18): 7512-25. [PMID:26334942]
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26. Ting KN, Blaylock NA, Sugden D, Delagrange P, Scalbert E, Wilson VG. (1999) Molecular and pharmacological evidence for MT1 melatonin receptor subtype in the tail artery of juvenile Wistar rats. Br J Pharmacol, 127: 987-995. [PMID:10433507]
27. Vanda Pharmaceuticals. Tasimelteon Advisory Committee Meeting Briefing Materials. Accessed on 08/10/2014. Modified on 08/10/2014. FDA, http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/PeripheralandCentralNervousSystemDrugsAdvisoryCommittee/UCM374388.pdf
Subcommittee members:Ralf Jockers (Chairperson) Philippe Delagrange Margarita L. Dubocovich Regina Pekelmann Markus Nicolas Renault Gianluca Tosini Darius Paul Zlotos |
Other contributors:Daniel P. Cardinali Diana N. Krause James Olcese Jesús Pintor David Sugden |
Database page citation (select format):
Concise Guide to PHARMACOLOGY citation:
Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Mathie AA, Peters JA, Veale EL, Armstrong JF, Faccenda E, Harding SD, Davies JA et al. (2023) The Concise Guide to PHARMACOLOGY 2023/24: G protein-coupled receptors. Br J Pharmacol. 180 Suppl 2:S23-S144.
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Melatonin, 2-iodo-melatonin, agomelatine, GR 196429, LY 156735 and ramelteon [14] are nonselective agonists for MT1 and MT2 receptors. (-)-AMMTC displays an ~400-fold greater agonist potency than (+)-AMMTC at rat MT1 receptors (see AMMTC for structure) [26]. Luzindole is an MT1/MT2 non-selective competitive melatonin receptor antagonist with about 15-25 fold selectivity for the MT2 receptor [8]. MT1/MT2 heterodimers present different pharmacological profiles from MT1 and MT2 receptors [2].
The MT3 binding site of hamster brain and peripheral tissues such as kidney and testis, also termed the ML2 receptor, binds selectively 2-iodo-[125I]5MCA-NAT [17]. Pharmacological investigations of MT3 binding sites have primarily been conducted in hamster tissues. At this site, The endogenous ligand N-acetylserotonin [10,16-17,20] and 5MCA-NAT [20] appear to function as agonists, while prazosin [16] functions as an antagonist. The MT3 binding site of hamster kidney was also identified as the hamster homologue of human quinone reductase 2 (NQO2, P16083 [18-19]). The MT3 binding site activated by 5MCA-NAT in eye ciliary body is positively coupled to adenylyl cyclase and regulates chloride secretion [12]. Xenopus melanophores and chick brain express a distinct receptor (x420, P49219; c346, P49288, initially termed Mel1C) coupled to the Gi/o family of G proteins, for which GPR50 has recently been suggested to be a mammalian counterpart [9] although melatonin does not bind to GPR50 receptors. Several variants of the MTNR1B gene have been associated with increased type 2 diabetes risk [13].