Recent advances in the development of melatonin MT1 and MT2 receptor agonists

Expert Opinion on Therapeutic Patents

Volumn 20, Issue 8, 2010, Pages 1059-1077

  Mor, Marco ^a   Rivara, Silvia ^a   Pala, Daniele ^a   Bedini, Annalida ^b   Spadoni, Gilberto ^b   Tarzia, Giorgio ^b  

^a UNIVERSITY OF PARMA   (Italy)

^b UNIVERSITY OF URBINO   (Italy)

Author keywords

Agomelatine; Circadian rhythm; Melatonin; Melatonin receptor agonists; Melatoninergic disorders; MT1; MT2; Ramelteon; Sleep disturbances

Indexed keywords

BENZOFURAN DERIVATIVE; BENZOTHIAZINE DERIVATIVE; BENZOXAZINE DERIVATIVE; CGC 031120; CGX 031120; HORMONE RECEPTOR STIMULATING AGENT; INDOLE DERIVATIVE; MELATONIN 1 RECEPTOR AGONIST; MELATONIN 2 RECEPTOR AGONIST; N [2 (6 METHOXY INDAN 1 YL)ETHYL]PROPIONAMIDE; N [2 (7 METHOXY D3) NAPHTHALEN 1 YL)ETHYL]ACETAMIDE D3; N [3 (3 METHOXYPHENYL)PROPYL]PROPIONAMIDE DERIVATIVE; RAMELTEON; TASIMELTEON; UNCLASSIFIED DRUG; CENTRAL NERVOUS SYSTEM AGENTS; LIGAND; MELATONIN 1 RECEPTOR; MELATONIN 2 RECEPTOR;

ANALGESIC ACTIVITY; ANTICONVULSANT ACTIVITY; CLINICAL TRIAL; CONTROLLED STUDY; DRUG BIOAVAILABILITY; DRUG SYNTHESIS; EPILEPSY; HUMAN; IC 50; NONHUMAN; PAIN; REVIEW; SLEEP DISORDER; STRUCTURE ACTIVITY RELATION; AGONISTS; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; DRUG DESIGN; PATENT;

ANIMALS; CENTRAL NERVOUS SYSTEM AGENTS; DRUG DESIGN; HUMANS; LIGANDS; MOLECULAR STRUCTURE; PATENTS AS TOPIC; RECEPTOR, MELATONIN, MT1; RECEPTOR, MELATONIN, MT2; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 77954949734     PISSN: 13543776     EISSN: None     Source Type: Journal    
DOI: 10.1517/13543776.2010.496455     Document Type: Review

References (109)

1. Inouye ST, Kawamura H. Persistence of circadian rhythmicity in a mammalian hypothalamic "island" containing the suprachiasmatic nucleus. Proc Natl Acad Sci USA 1979;76:5962-5966
2. Cardinali DP, Rosner JM. Metabolism of serotonin by the rat retina "in vitro". J Neurochem 1971;18:1769-1770
3. Tosini G, Menaker M. The clock in the mouse retina: melatonin synthesis and photoreceptor degeneration. Brain Res 1998;789:221-228
4. Carrillo-Vico A, Calvo JR, Abreu P, et al. Evidence of melatonin synthesis by human lymphocytes and its physiological significance: possible role as intracrine, autocrine and/or paracrine substance. FASEB J 2004;18:537-539
5. Raikhlin NT, Kvetnoy IM. Melatonin and enterochromaffine cells. Acta Histochem 1976;55:19-24
6. Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 2002;47:2336-2348
7. Reiter RJ. The pineal and its hormones in the control of reproduction in mammals. Endocr Rev 1980;1:109-131
8. Gillette MU, Tischkau SA. Suprachiasmatic nucleus: the brain's circadian clock. Recent Prog Horm Res 1999;54:33-58
9. Shochat T, Luboshitzky R, Lavie P. Nocturnal melatonin onset is phase locked to the primary sleep gate. Am J Physiol 1997;273:R364-70
10. Krauchi K, Wirz-Justice A. Circadian clues to sleep onset mechanism. Neuropsychopharmacology 2001;25:S92-6
11. Ferguson SA, Rajaratnam SMW, Dawson D. Melatonin agonists and insomnia. Expert Rev Neurother 2010;10:305-318
12. Rajaratnam SMW, Cohen DA, Rogers NL. Melatonin and melatonin analogues. Sleep Med Clin 2009;4:179-193
13. Maestroni GJ. The immunotherapeutic potential of melatonin. Expert Opin Investig Drugs 2001;10:467-476
14. Arangino S, Cagnacci A, Angiolucci M, et al. Effects of melatonin on vascular reactivity, catecholamine levels and blood pressure in healthy men. Am J Cardiol 1999;83:1417-1419
15. Cagnacci A, Arangino S, Angiolucci M, et al. Effect of exogenous melatonin on vascular reactivity and nitric oxide in postmenopausal women: role of hormone replacement therapy. Clin Endocrinol (Oxf) 2001;54:261-266
16. Ambriz-Tututi M, Rocha-Gonzalez HI, Cruz SL, Granados-Soto V. Melatonin: a hormone that modulates pain. Life Sci 2009;84:489-498
17. Satomura K, Tobiume S, Tukoyama R, et al. Melatonin at pharmacological doses enhances human osteoblastic differentiation in vitro and promotes mouse cortical bone formation in vivo. J Pineal Res 2007;42:231-239
18. Korkmaz A, Reiter RJ, Topal T, et al. Melatonin: an established antioxidant worthy of use in clinical trials. Mol Med 2009;15:43-50
19. Dubocovich ML, Cardinali DP, Delagrange P, et al. Melatonin receptors. The IUPHAR compendium of receptor characterization and classification. IUPHAR Media, London; 2001. p. 270-277
20. Tan DX, Manchester LC, Terron MP, et al. Melatonin as a naturally occurring co-substrate of quinone reductase-2, the putative MT3 melatonin membrane receptor: hypothesis and significance. J Pineal Res 2007;43:317-320
21. Benitez-King G, Huerto-Delgadillo L, Anton-Tay F. Binding of 3H-melatonin to calmodulin. Life Sci 1993;53:201-207
22. Romero MP, Garcia-Perganeda A, Guerrero JM, Osuna C. Membrane-bound calmodulin in Xenopus laevis oocytes as a novel binding site for melatonin. FASEB J 1998;12:1401-1408
23. Hardeland R. Melatonin: signaling mechanisms of a pleiotropic agent. Biofactors 2009;35:183-192
24. Witt-Enderby PA, Bennett J, Jarzynka MJ, et al. Melatonin receptors and their regulation: biochemical and structural mechanisms. Life Sci 2003;72:2183-2198
25. Weaver DR, Reppert SM. The Mel1a melatonin receptor gene is expressed in human suprachiasmatic nuclei. Neuroreport 1996;8:109-112
26. Savaskan E, Ayoub MA, Jockers R, et al. Reduced hippocampal MT2 melatonin receptor expression in Azheimer's disease. J Pineal Res 2005;38:10-16
27. Uz T, Arslan AD, Imbesi M, et al. The regional and cellular expression profile of the melatonin receptor MT1 in the central dopaminergic system. Brain Res Mol Brain Res 2005;136:45-53
28. Ekmekcioglu C, Thalhammer T, Humpeler S, et al. The melatonin receptor subtype MT2 is present in the human cardiovascular system. J Pineal Res 2003;35:40-44
29. Savaskan E, Wirz-Justice A, Olivieri G, et al. Distribution of melatonin MT1 receptor immunoreactivity in human retina. J Histochem Cytochem 2002;50:519-526
30. Maestroni GJ, Sulli A, Pizzorni C, et al. Melatonin in rheumatoid arthritis: synovial macrophages show melatonin receptors. Ann NY Acad Sci 2002;966:271-275
31. Jin X, von Gall C, Pieschl RL, et al. Targeted disruption of mouse Mel1b melatonin receptor. Mol Cell Biol 2003;23:1054-1060
32. von Gall C, Garabette ML, Kell CA, et al. Rhythmic gene expression in pituitary depends on heterologous sensitization by the neurohormone melatonin. Nat Neurosci 2002;5:234-238
33. Drazen DL, Bilu D, Bilbo SD, Nelson RJ. In vitro melatonin enhancement of splenocyte proliferation is attenuated in mice by luzindole, a melatonin receptor antagonist. Am J Physiol 2001;280:R1476-82
34. Dubocovich ML, Masana MI, Iacob S, Sauri DM. 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-Schmied Arch Pharmacol 1997;355:365-375
35. Ersahin C, Masana MI, Dubocovich ML. Constitutively active melatonin MT1 receptors in male rat caudal artieries. Eur J Pharmacol 2002;439:171-172
36. Masana MI, Doolen S, Ersahin C, et al. MT2 melatonin receptors are present and functional in rat caudal artery. J Pharmacol Exp Ther 2002;302:1295-1302
37. Srinivasan V, Pandi-Perumal SR, Trahkt I, et al. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci 2009;119:821-846
38. Lewy AJ. Circadian misalignment in mood disturbances. Curr Psychiatry Rep 2009;11:459-465
39. Hirsch-Rodriguez E, Imbesi M, Manev R, et al. The pattern of melatonin receptor expression in the brain may influence antidepressant treatment. Med Hypotheses 2006;69:120-124
40. Solmaz I, Gurkanlar D, Gokcil Z, et al. Antiepileptic activity of melatonin in guinea pigs with pentylenetetrazol-induced seizures. Neurol Res 2009;31:989-995
41. Lin HW, Lee EJ. Effects of melatonin in experimental stroke models in acute, sub-acute, and chronic stages. Neuropsychiatr Dis Treat 2009;5:157-162
42. Kiefer TL, Ram PT, Yuan L, Hill SM. Melatonin inhibits estrogen receptor transactivation and cAMP levels in breast cancer cells. Breast Cancer Res Treat 2002;71:37-45
43. Garcia-Navarro A, Gonzalez-Puga C, Escames G, et al. Cellular mechanisms involved in the melatonin inhibition of HT-29 human colon cancer cell proliferation in culture. J Pineal Res 2007;43:195-205
44. Spadoni G, Bedini A, Mor M, Rivara S. The rationale for the development of melatonin receptor ligands. In: Pandi-Perumal SR, Verster JC, Monti JM, et al., editors, Sleep disorders: diagnosis and therapeutics. Informa Healthcare, London; 2008
45. Steinhilber D, Carlberg C. Melatonin receptor ligands. Expert Opin Ther Patents 1999;9:281-290
46. Hardeland R. Investigational melatonin receptor agonists. Expert Opin Investig Drugs 2010;19:747-764
47. Rajaratnam SM, Polymeropoulos MH, Fisher DM, et al. Melatonin agonist tasimelteon (VEC-162) for transient insomnia after sleep-time shift: two randomised controlled multicentre trials. Lancet 2009;373:482-491
48. Available from: www.vandapharma.com/development.html
49. Zemlan FP, Mulchahey JJ, Scharf MB, et al. The efficacy and safety of the melatonin agonist beta-methyl-6-chloromelatonin in primary insomnia: a randomized, placebo-controlled, crossover clinical trial. J Clin Psychiatry 2005;66:384-390
50. Tarzia G, Mor M, Rivara S, et al. Melatonin receptor agonists: SAR and application to the treatment of sleep-wake disorders. Curr Top Med Chem 2008;8:954-968
51. Zlotos DP. Recent advances in melatonin receptor ligands. Arch Pharm (Weinheim) 2005;338:229-247
52. Davies DJ, Faust R, Garratt PJ, et al. Binding affinity and biological activity of oxygen and sulfur isosteres at melatonin receptors as a function of their hydrogen bonding capability. Bioorg Chem 2004;32:1-12
53. Les Laboratoires Servier. Novel indole derivatives, process for their preparation thereof and pharmaceutical compositions containing them. WO2008049997; 2008
54. Elsner J, Boeckler F, Davidson K, et al. Bicyclic melatonin receptor agonists containing a ring-junction nitrogen: synthesis, biological evaluation, and molecular modeling of the putative bioactive conformation. Bioorg Med Chem 2006;14:1949-1958
55. Tsotinis A, Panoussopoulou M, Sivananthan S, Sugden D. Synthesis of new tricyclic melatoninergic ligands. Farmaco 2001;56:725-729
56. Tsotinis A, Panoussopoulou M, Hough K, et al. Synthesis and biological evaluation of new beta,beta'-disubstituted 6,7,8,9-tetrahydropyrido[1,2-a]indol- 10-yl ethylamido melatoninergic ligands. Eur J Pharm Sci 2003;18:297-304
57. Spadoni G, Balsamini C, Diamantini G, et al. Conformationally restrained melatonin analogues: synthesis, binding affinity for the melatonin receptor, evaluation of the biological activity, and molecular modeling study. J Med Chem 1997;40:1990-2002
58. Rivara S, Diamantini G, Di Giacomo B, et al. Reassessing the melatonin pharmacophore-enantiomeric resolution, pharmacological activity, structure analysis, and molecular modeling of a constrained chiral melatonin analogue. Bioorg Med Chem 2006;14:3383-3391
59. Cognetix, Inc. Subtype selective melatonergics. WO0200215; 2002
60. Faust R, Garratt PJ, Jones R, et al. Mapping the melatonin receptor. 6. Melatonin agonists and antagonists derived from 6H-isoindolo[2,1-a]indoles, 5,6-dihydroindolo[2,1-a]isoquinolines, and 6,7-dihydro-5H-benzo[c]azepino [2,1-a]indoles. J Med Chem 2000;43:1050-1061
61. Fisher SP, Sugden D. Sleep-promoting action of IIK7, a selective MT2 melatonin receptor agonist in the rat. Neurosci Lett 2009;457:93-96
62. Ferrer Internacional S.A. Compounds of 2,3-dihydro-benzofuran. WO2009053444; 2009
63. Ferrer Internacional S.A. Indane compounds. WO2009053443; 2009
64. Ferrer Internacional S.A. Indoline compounds. WO2009053440; 2009
65. Glaxo Group, Ltd. Indoline derivatives, method of preparation and use. US5633276; 1997
66. Epperson JR, Bruce MA, Catt JD, et al. Chronobiotic activity of N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]-propanamide. Synthesis and melatonergic pharmacology of fluoren-9-ylethyl amides. Bioorg Med Chem 2004;12:4601-4611
67. Bristol-Myers Squibb Co. Polycyclic ethyl alkylamide melatonergic agents. US5948817; 1999
68. Bristol-Myers Squibb Co. Spirocyclopropyl fluorenes as melatonergic agents. US6028112; 2000
69. Concert Pharmaceuticals, Inc. Naphtyl (ethyl) acetamides. WO2008137461; 2008
70. Les Laboratoires Servier. Novel naphthalene derivatives, process for the preparation thereof and pharmaceutical compositions containing same. WO2009022062; 2009
71. Les Laboratoires Servier. Novel naphthalene derivatives, process for the preparation thereof and pharmaceutical compositions containing same. WO2009022066; 2009
72. Les Laboratoires Servier. Novel naphthalene derivatives, process for the preparation thereof and pharmaceutical compositions containing same. WO2009022064; 2009
73. Les Laboratoires Servier. Novel naphthalene derivatives, process for the preparation thereof and pharmaceutical compositions containing same. WO2009022063; 2009
74. Les Laboratoires Servier. Novel naphthalene derivatives, process for the preparation thereof and pharmaceutical compositions containing same. WO2009022065; 2009
75. Jellimann C, Mathe-Allainmat M, Andrieux J, et al. Synthesis of phenalene derivatives as new conformationally restricted ligands for melatonin receptors. J Med Chem 2000;43:4051-4062
76. Mesangeau C, Peres B, Descamp-Francois C, et al. Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT1 melatoninergic ligands. Bioorg Med Chem 2010;18:3426-3436
77. Adir et Compagnie. Substituted dimeric compounds. US6319930; 2001
78. Audinot V, Mailliet F, Bonnaud A, et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn-Schmied Arch Pharmacol 2003;367:553-561
79. Les Laboratoires Servier. Novel bicyclic alkyl derivatives, method for production of and pharmaceutical compositions comprising the same. WO2005012229; 2005
80. Mattson RJ, Catt JD, Keavy D, et al. Indanyl piperazines as melatonergic MT2 selective agents. Bioorg Med Chem Lett 2003;13:1199-1202
81. Les Laboratoires Servier. Substituted (dihydro)benzoxazine and (dihydro) benzothiazine compounds. US6620809; 2003
82. Wyeth. Dihydrobenzofuran derivatives and uses thereof. W02006116136; 2006
83. The Hong Kong University of Science and Technology. Isoquinolone compounds as subtype-selective agonists for melatonin receptors MT1 and MT2. WO2008092292; 2008 84.
84. Bristol-Myers Squibb Co. Benzofuran and dihydrobenzofuran melatonergic agents. US5856529; 1999
85. Bristol-Myers Squibb Co. Benzopyran derivatives as melatonergic agents. US6060506; 2000
86. Bristol-Myers Squibb Co. Benzodioxa alkylene ethers as melatonergic agents. US5981571; 1999
87. Bristol-Myers Squibb Co. Heterocyclic cis cyclopropane derivatives as melatonergic agents. W09962515; 1999
88. Bristol-Myers Squibb Co. Arylalkylbenzofuran derivatives as melatonergic agents. US6569894; 2003
89. Sun L-Q, Takaki K, Chen J, et al. (R)-2-(4-Phenylbutyl)dihydrobenzofuran derivatives as melatoninergic agents. Bioorg Med Chem Lett 2005;15:1345-1349
90. Sun L-Q, Takaki K, Chen J, et al. N-{2-[2-(4-Phenylbutyl)benzofuran-4-yl] cyclopropylmethyl}-acetamide: an orally bioavailable melatonin receptor agonist. Bioorg Med Chem Lett 2004;14:5157-5160
91. Bristol-Myers Squibb Co. Benzoxazole derivatives as novel melatonergic agents. US6737431; 2004
92. Sun L-Q, Chen J, Takaki K, et al. Design and synthesis of benzoxazole derivatives as novel melatoninergic ligands. Bioorg Med Chem Lett 2004;14:1197-1200
93. Sun L-Q, Chen J, Bruce M, et al. Synthesis and structure-activity relationship of novel benzoxazole derivatives as melatonin receptor agonists. Bioorg Med Chem Lett 2004;14:3799-3802
94. Bristol-Myers Squibb. Heterocyclic aminopyrrolidine derivatives as melatonergic agents. US6211225; 2001
95. Luo G, Sun L-Q, Chen J, et al. Heterocyclic aminopyrrolidine derivatives as melatoninergic agents. Bioorg Med Chem Lett 2003;13:4381-4384
96. Vanda Pharmaceuticals, Inc. Treatment for depressive disorders. WO2007137247; 2007
97. Takeda Pharmaceutical Co., Ltd. Bicyclic compound and pharmaceutical use thereof. WO2008136382; 2008
98. Takeda Pharmaceutical Co., Ltd. Tricyclic compound and medical use thereof. W02008069311; 2008
99. Takeda Pharmaceutical Co., Ltd. Tricyclic compound and pharmaceutical use thereof. WO2008084717; 2008
100. Ferrer Internacional S.A. 1,6-dihydro-2H-3-oxa-6-aza-as-indacene compounds. W02010012789; 2010
101. Takeda Chemical Industries, Ltd. Tricyclic compounds, their production and use. US6034239; 2000
102. Takeda Pharmaceutical Co., Ltd. Tricyclic compound and pharmaceutical use thereof. W02007148808; 2007
103. Bristol-Myers Squibb Co. N-acyl-2-arylcyclopropylmethylamine derivatives as melatonergics. US5889031; 1999
104. Ferrer Internacional S.A. Phenylpyrrolidine compounds. W02009053441; 2009
105. Bristol-Myers Squibb Co. Aryloxyanilides and related compounds. W09948859; 1999
106. Epperson JR, Deskus JA, Gentile AJ, et al. 4-substituted anilides as selective melatonin MT2 receptor agonists. Bioorg Med Chem Lett 2004;14:1023-1026
107. McGill University, Universita degli Studi di Parma, Universita degli Studi di Milano, Universita degli Studi di Urbino. Novel melatonin ligands having antidepressant activity as well as sleep inducing properties. W02007079593; 2007
108. Rivara S, Lodola A, Mor M, et al. N-(substituted-anilinoethyl)amides: design, synthesis, and pharmacological characterization of a new class of melatonin receptor ligands. J Med Chem 2007;50:6618-6626
109. Hu Y, Ho MKC, Chan KH, et al. Synthesis of substituted N-[3-(3-methoxyphenyl)propyl] amides as highly potent MT2-selective melatonin ligands. Bioorg Med Chem Lett 2010;20:2582-2585