Melatonin receptor agonists: SAR and applications to the treatment of sleep-wake disorders

Current Topics in Medicinal Chemistry

Volumn 8, Issue 11, 2008, Pages 954-968

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

^a UNIVERSITY OF PARMA   (Italy)

^b UNIVERSITY OF URBINO   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

2 BROMOMELATONIN; 2 IODOMELATONIN; 6 CHLOROMELATONIN; AGOMELATINE; ALCOHOL; BENZODIAZEPINE; BETA METHYL 6 CHLOROMELATONIN; ESZOPICLONE; G PROTEIN COUPLED RECEPTOR; HORMONE RECEPTOR STIMULATING AGENT; INDIPLON; MELATONIN; MELATONIN 1 RECEPTOR; MELATONIN 1 RECEPTOR AGONIST; MELATONIN 2 RECEPTOR; MELATONIN 2 RECEPTOR AGONIST; MELATONIN DERIVATIVE; N [2 [(3 METHOXYPHENYL)PHENYLAMINO]ETHYL]ACETAMIDE; PAROXETINE; PLACEBO; PROPOFOL; RAMELTEON; TIK 301; UCM 765; VEC 162; VENLAFAXINE; ZOLPIDEM;

ABNORMAL BEHAVIOR; AMNESIA; ANIMAL MODEL; ANTIOXIDANT ACTIVITY; CIRCADIAN RHYTHM; CIRCADIAN RHYTHM SLEEP DISORDER; CLINICAL TRIAL; DAYTIME SOMNOLENCE; DIZZINESS; DRUG ALCOHOL INTERACTION; DRUG EFFICACY; DRUG HALF LIFE; DRUG INDUCED HEADACHE; DRUG RECEPTOR BINDING; DRUG STRUCTURE; DRUG TARGETING; EVENING DOSAGE; FATIGUE; HUMAN; INSOMNIA; MENTAL DISEASE; NAUSEA; NONHUMAN; REVIEW; SLEEP DISORDER; STRUCTURE ACTIVITY RELATION;

HUMANS; HYPNOTICS AND SEDATIVES; MELATONIN; RECEPTORS, MELATONIN; SLEEP INITIATION AND MAINTENANCE DISORDERS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 48249086074     PISSN: 15680266     EISSN: None     Source Type: Journal    
DOI: 10.2174/156802608784936719     Document Type: Review

References (161)

1. McCord, C. P.; Allen, F. P. Evidence associating pineal gland function with alterations in pigmentation. J. Exp. Zool. 1917, 23, 207-224.
2. Lerner, A. B.; Case, J. D.; Takahashi Y.; Lee, T. H.; Mori, W. Isolation of melatonin, the pineal gland factor that lightens melanocytes. J. Am. Chem. Soc. 1958, 80, 2587.
3. Lerner, A. B.; Case, J. D. Structure of melatonin. J. Am. Chem. Soc. 1959, 81, 6084.
4. Hardeland, R.; Poeggeler, B. Non-vertebrate melatonin. J. Pineal Res. 2003, 34, 233-241.
5. Utiger, R. D. Melatonin - The hormone of darkness. N. Engl. J. Med. 1992, 327, 1377-1379.
6. Axerold, J. The pineal gland: A neurochemical transducer. Science 1974, 184, 1341-1348.
7. Claustrat, B.; Brun, J.; Chazot, G. The basic physiology and pathophysiology of melatonin. Sleep. Med. Rev. 2005, 9, 11-24.
8. Pandi-Perumal, S. R.; Srinivagan, V.; Maestroni, G. J. M.; Cardinali, D. P.; Poeggeler, B.; Hardeland, R. Melatonin: Nature's most versatile biological signal? FEBS J. 2006, 273, 2813-2838.
9. Hirata, F.; Hayaishi, O.; Tokuyama, T.; Seno, S. In vitro and in vivo formation of two new metabolites of melatonin. J. Biol. Chem. 1974, 249, 1311-1313.
10. Wher, T. A. Melatonin and seasonal rhythms. J. Biol. Rhythms 1997, 12, 518-527.
11. Herxheimer, A.; Petrie, K. J. Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst. Rev. 2002; (2): CD001520.
12. Cardinali, D. P.; Brusco, L. I.; Lloret, S. P.; Furio, A. M. Melatonin in sleep disorders and jet-lag. Neuroendocrinol. Lett. 2002, 23 Suppl 1, 9-13.
13. Zisapel, N. Circadian rhythm sleep disorders: Pathophysiology and potential approaches to management. CNS Drugs 2001, 15, 311-328.
14. Sack, R. L.; Lewy, A. J. Melatonin as a chronobiotic: Treatment of circadian desynchrony in night workers and the blind. J. Biol. Rhythms 1997, 12, 595-603.
15. Molina-Carballo, A.; Muñoz-Hoyos, A.; Reiter, R. J.; Sánchez-Forte, M.; Moreno-Madrid, F.; Rufo-Campos, M,; Molina-Font J. A.; Acuña-Castroviejo, D. Utility of high doses of melatonin as adjunctive anticonvulsant therapy in a child with severe myoclonic epilepsy: Two years' experience. J. Pineal Res. 1997, 23, 97-105.
16. Claustrat, B.; Chazot, G.; Brun, J.; Jordan, D.; Sassolas, G. A. Chronobiological study of melatonin and cortisol secretion in depressed subjects: Plasma melatonin, a biochemical marker in major depression. Biol. Psychiatry 1984, 19, 1215-1228.
17. Srinivasan, V.; Smits, M.; Spence, W.; Lowe, A. D.; Kayumov, L.; Pandi-Perumal, S. R.; Parry, B.; Cardinali, D. P. Melatonin in mood disorders. World J. Biol. Psychiatry 2006, 7, 138-151.
18. Fiorina, P.; Lattuada, G.; Silvestrini, C.; Ponari, O.; Dall'Aglio, P. Disruption of nocturnal melatonin rhythm and immunological involvement in ischaemic stroke patients. Scand. J. Immunol. 1999, 50, 228-231.
19. Peres, M. F. P.; Masruha, M. R.; Zukerman, E.; Moreira-Filho, C. A.; Cavalheiro, E. A. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin. Investig. Drugs 2006, 15, 367-375.
20. Scheer, F. A.; Van Montfrans, G. A.; van Someren, E. J.; Mairuhu, G.; Buijs, R. M. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 2004, 43, 192-197.
21. Carrillo-Vico, A.; Reiter, R. J.; Lardone, P. J.; Herrera J. L.; Fernández-Montesinos, R.; Guerrero, J. M.; Pozo, D. The modulatory role of melatonin on immune responsiveness. Curr. Opin. Investig. Drugs 2006, 7, 423-431.
22. Alarma-Estrany, P.; Pintor, J. Melatonin receptors in the eye: Location, second messengers and role in ocular physiology. Pharmacol. Ther. 2007, 113, 507-522.
23. Jung, B.; Ahmad, N. Melatonin in cancer management: Progress and promise. Cancer Res. 2006, 66, 9789-9793.
24. Rawashdeh, O.; Hernandez de Borsetti, N.; Roman, G.; Cahill, G. M. Melatonin suppresses nighttime memory formation in zebrafish. Science 2007, 318, 1144-1146.
25. Sofic, E.; Rimpapa, Z.; Kundurovic, Z.; Sapcanin, A.; Tahirovic, I.; Rustembegovic, A.; Cao G. Antioxidant capacity of the neurohormone melatonin. J. Neural Transm. 2005, 112, 349-358.
26. Srinivasan, V.; Pandi-Perumal, S.; Cardinali, D. Melatonin in Alzheimer's disease and other neurodegenerative disorders. Behav. Brain Funct. 2006, 2, 15.
27. 125I-melatonin. FEBS Lett. 1986, 197, 9-12.
28. Vakkuri, O.; Lämsa, E.; Rahkamaa, E.; Ruotsalainen, H.; Leppaluoto, J. Iodinated melatonin: Preparation and characterization of the molecular structure by mass and 1H NMR spectroscopy. Anal. Biochem. 1984, 142, 284-289.
29. Vakkuri, O.; Leppaluoto, J.; Vuolteenaho, O. Development and validation of a melatonin radioimmunoassay using radioiodinated melatonin as tracer. Acta Endocrinol. (Copenh) 1984, 106, 152-157.
30. Nonno, R.; Capsoni, S.; Lucini, V.; Møller, M.; Fraschini, F.; Stankov, B. Distribution and characterization of the melatonin receptors in the hypothalamus and pituitary gland of three domestic ungulates. J. Pineal Res. 1995, 18, 207-216.
31. Morgan, P. J.; Barrett, P.; Howell, H. E.; Helliwell, R. Melatonin receptors: Localization, molecular pharmacology and physiological significance. Neurochem. Int. 1994, 24, 101-146.
32. Reppert, S. M.; Weaver, D. R.; Godson, C. Melatonin receptors step into the light: Cloning and classification of subtypes. Trends Pharmacol. Sci. 1996, 17, 100-102.
33. Dubocovich, M. L.; Cardinali, D. P.; Delagrange, P.; Krause, D. N.; Strosberg, A. D.; Sugden, D.; Yocca, F. D. The IUPHAR compendium of receptor characterization and classification. IUPHAR Media, London 2000, pp 271-277.
34. 125I]iodomelatonin binding sites in Syrian hamster peripheral organs. J. Pharmacol. Exp. Ther. 1999, 290, 334-340.
35. 3 as the quinone reductase 2. J. Motl Chem. 2000, 275, 31311-31317.
36. Paz Romero, M.; Garcia-Pergañeda, A.; Guerrero, J. M.; Osuna, C. Membrane-bound calmodulin in Xenopus laevis oocytes as a novel binding site for melatonin. FASEB J. 1998, 12, 1401-1408.
37. Reppert, S. M.; Weaver, D. R.; Ebisawa, T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 1994, 13, 1177-1185.
38. 1b melatonin receptor. Proc. Natl. Acad. Sci. 1995, 92, 8734-8738.
39. Von Gall, C.; Stehle, J. H.; Weaver, D. R. Mammalian melatonin receptors: Molecular biology and signal transduction. Cell Tissue Res. 2002, 309, 151-162.
40. McArthur, A. J.; Hunt A. E.; Gillette, M. U. Melatonin action and signal transduction in the rat suprachiasmatic; circadian clock: Activation of protein kinase C at dusk and dawn. Endocrinol. 1997, 138, 627-634.
41. Ekmekcioglu, C. Melatonin receptors in humans: Biological role and clinical relevance. Biomed Pharmacother. 2006, 60, 97-108.
42. Dubocovich, M. L.; Benloucif, S.; Masana, M. I. Melatonin receptors in the mammalian suprachiasmatiic nucleus. Behav. Brain Res. 1996, 73, 141-147.
43. Doolen S.; Krause, D. N.; Dubocovich, M. L.; Duckles, S. P. Melatonin mediates two distinct responses in vascular smooth muscle. Eur. J. Pharmacol. 1998, 345, 67-69.
44. Liu, C.; Weaver, D. R.; An, X.; Shearman, L. P.; Pieschl, R. L.; Gribkoff, V. K.; Reppert, S. M. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 1997, 19, 91-102.
45. 2 melatonin receptor antagonists block melatonin-mediated phase advances of circadian rhythms. FASEB J 1998, 12, 1211-1220.
46. Sugden, D. Aggregation of pigment granules in single cultured Xenopus laevis melanophores by melatonin analogs. Br. J Pharmacol. 1991, 104, 922-927.
47. Dubocovich, M. L. Melatonin is a potent modulator of dopamine release in the retina. Nature 1984, 306, 792-794.
48. Krause, D. N.; Barrios, V. E.; Duckles, S. P. Melatonin receptors mediate potentiation of contractile responses to adrenergic nerve stimulation in rat caudal artery. Eur. J. Pharmacol. 1995, 276, 207-213.
49. Hunt, A. E.; Al-Ghoul, W. M.; Gillette, M. U.; Dubocovich, M. L. Activation of MT2 melatonin receptors in rat suprachiasmatic nucleus phase advances the circadian clock. Am J. Physiol. 2001, 280, C110-C118.
50. 2 receptors. Br. J. Pharmacol., 2000, 129, 877-886.
51. 2 selective agents. Bioorg. Med. Chem. Lett. 2003, 13, 1199-1202.
52. l -antagonists. Br. J. Pharmacol. 1999, 127, 1288-1294.
53. 35S]-GTPγS binding. Biochem. Pharmacol. 1998, 56, 1167-1174.
54. 125I]iodomelatonin to characterize melatonin binding sites in chicken retina. Proc. Natl. Acad. Sci. 1987, 84, 3916-3920.
55. Nonno, R.; Lucini, V.; Pannacci, M.; Mazzucchelli, C.; Angeloni, D.; Fraschini, F.; Stankov B. M. Pharmacological characterization of the human melatonin Mella receptor following stable transfection into NIH3T3 cells. Br. J. Pharmacol. 1998, 124, 485-492.
56. http://consensus.nih.gov/2005/2005InsomniaSOS026html.htm
57. Drake, C. L.; Roehrs, T.; Roth, T. Insomnia causes, consequences, and therapeutics: An overview. Depress. Anxiety 2003, 18, 163-176.
58. Gershell, L. Insomnia market. Nat. Rev. Drug Discov. 2006, 5, 15-16.
59. Lerner, A. B.; Case, J. C. Melatonin. Fed. Proc. 1960, 19, 590-592.
60. Anton-Tay, F.; Diaz, J. L.; Fernandez-Guardiola, A. On the effect of melatonin upon the human brain: Its possible therapeutic implications. Life Sci. 1971, 10, 841-850.
61. Zhdanova, I. V. Melatonin as a hypnotic: Pro. Sleep Med. Rev. 2005, 9, 51-65.
62. van den Heavel, C. J.; Ferguson, S, A.; Macchi, M. M.; Dawson, D. Melatonin as a hypnotic: Con. Sleep Med. Rev. 2005, 9, 71-80.
63. Steinhilberg, D.; Carlberg, C. Melatonin receptor ligands. Exp. Opin. Ther. Patents 1999, 9, 281-290.
64. Mor, M.; Plazzi, P. V.; Spadoni, G.; Tarzia, G. Melatonin. Curr. Med. Chem. 1999, 6, 501-518.
65. Witt-Enderby, P. A.; Li, P.-K. Melatonin receptors and ligands. Vitam. Horm. 2000, 58, 321-354.
66. Zlotos, D. P. Recent advances in melatonin receptor ligands. Arch. Pharm. Chem. Life Sci. 2005, 338, 229-247.
67. Lira-Rocha, A.; Espejo-González, O.; Naranjo-Rodriguez, E. B. Receptor-binding studies of 1-N-substituted melatonin analogues. Eur. J. Med. Chem. 2002, 37, 945-951.
68. 2 melatonin receptor ligands: Requirements for subtype selectivity and intrinsic activity modulation. J. Med. Chem. 2003, 46, 1429-1439.
69. Spadoni, G.; Stankov, B.; Duranti, A.; Biella, G.; Lucini, V.; Salvatori, A.; Fraschini, F. 2-Substituted 5-methoxy-N-acyltryptamines: synthesis, binding affinity for the melatonin receptor, and evaluation of the biological activity. J. Med. Chem. 1993, 36, 4069-4074.
70. Duranti, E.; Stankov, B.; Spadoni, G.; Duranti, A.; Lucini, V.; Capsoni, S.; Biella, G.; Fraschini, F. 2-Bromomelatonin: Synthesis and characterization of a potent melatonin agonist. Life Sci. 1992, 51, 479-485.
71. 1 presynaptic heteroreceptor. Naunyn-Schmiedeberg's Arch. Pharmacol. 1997, 355, 365-375.
72. Garratt, P- J.; Jones, R.; Rowe, S. J.; Sugden, D. Mapping the melatonin receptor. 1. The 5-methoxyl group of melatonin is not an essential requirement for biological activity. Bioorg. Med. Chem. Lett., 1994, 4, 1555-1558.
73. Sugden, D.; Chong, N. W. S.; Lewis, D. F. V. Structural requirements at the melatonin receptor. Br. J. Pharmacol. 1995, 114, 618-623.
74. Davies, D. J.; Faust R.; Garratt, P. J.; Marivingt-Mounir, C.; Davidson, K.; Teh, M.-T.; Sugden, D. 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.
75. Sugden, D.; Pickering, H.; Teh, M.-T.; Garratt, P.- J. Melatonin receptor pharmacology: Toward subtype specificity. Biol. Cell 1997, 89, 531-537.
76. 2 melatonin receptors. Med. Chem. Res. 1998, 8, 487-498.
77. Spadoni, G.; Mor, M.; Tarzia, G. Structure-affinity relationships of indole-based melatonin analogs. Biol. Signals Recept. 1999, 8, 15-23.
78. Nosjean, O.; Nicolas, J. P.; Klupsch, F.; Delagrange, P.; Canet, E.; Boutin, J. A. Comparative pharmacological studies of melatonin receptors: MT1, MT2 and MT3/QR2. Tissue distribution of MT3/QR2. Biochem. Pharmacol. 2001, 61, 1369-1379.
79. Faust R.; Garratt, P. J.; Trujillo Pérez, M- A.; Piccio, V. J.-D.; Madsen, C.; Stenstrøm, A.; Frølund, B.; Davidson, K.; Teh, M-T.; Sugden, D. 7-Substituted-melatonin and 7-substituted-l-methylmelatonin analogues: Effect of substituents on potency and binding affinity. Bioorg. Med. Chem. 2007, 15, 4543-4551.
80. Tsotinis, A.; Vlachou, M.; Papahatjis, D. P.; Calogeropoulou, T.; Nikas, S. P.; Garratt, P. J.; Piccio, V.; Vonhoff, S.; Davidson, K; Teh, M.-T.; Sugden, D. Mapping the melatonin receptor. 7. Subtype selective ligands based on β-substituted N-acyl-5-medioxy-tryptamines and β-substituted N-acyl-5-methoxy-1-methyltryptamines. J. Med. Chem. 2006, 49, 3509-3519.
81. Flaugh, M. E.; Bruns, R. F.; Clarke, D. O.; Goldberg, M. J.; Shipley, L. A.; Nelson, D. L: G:; Nickelsen, T. N.; Levine, L. R. Preliminary clinical studies on the melatonin agonist LY156735. Gordon Research Conference on Pineal Cell Biology, 2000, Oxford, UK.
82. Mulchahey, J. J.; Goldwater, D. R.; Zemlan, F. P. A single blind, placebo controlled, across groups dose escalation study of the safety, tolerability, pharmacokinetics and pharmacodynamics of the melatonin analog β-methyl-6-chloromelatonin. Life Sci 2004, 75, 1843-1856.
83. Garratt, P- J.; Jones, R.; Tocher, D. A. Mapping the melatonin receptor. 3. Design and synthesis of melatonin agonists and antagonists derived from 2-phenylbyptamines. J. Med. Chem. 1995, 38, 1132-1139.
84. Navajas, C.; Kokkola, T.; Poso, A.; Honka, N.; Gynther, J.; Laitinen, J. T. A rhodopsin-based model for melatonin recognition at its G protein-coupled receptor. Eur. J. Pharmacol. 1996, 304, 173-183.
85. Depreux, P.; Lesieur, D.; Mansour, H. A.; Morgan, P.; Howell, H. E.; Renard, P.; Caignard, D.-H.; Pfeiffer, B.; Delagrange, P.; Guardiola, B.; Yous, S.; Demarque, A.; Adam, G.; Andrieux, J. Synthesis and structure-activity relationships of novel naphthalenic and bioisosteric related amidic derivatives as melatonin receptor ligands. J. Med. Chem. 1994, 37, 3231-3239.
86. Tarzia, G.; Diamantini, G.; Di Giacomo, B.; Spadoni, G.; Esposti, D.; Nonno, R.; Lucini, V.; Pannacci, M.; Fraschini, F.; Stankov, B. M. 1-(2-Alkanamidoethyl)-6-methoxyindole derivatives: A new class of potent indole melatonin analogues. J. Med. Chem. 1997, 40, 2003-2010.
87. Elsner, J.; Boeckler, F.; Davidson, K.; Sugden, D.; Gmeiner, P. 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.
88. Beresford, I. J. M.; Browning, C.; Starkey, S. J.; Brown, J.; Foord, S. M.; Coughlan, J.; North, P. C.; Dubocovich, M. L.; Hagan, R. M. GR196429: A nonindolic agonist at high-affinity melatonin receptors. J. Pharmacol. Exp. Ther. 1998, 285, 1239-1245.
89. Davies, D. J.; Garratt, P. J.; Tocher, D. A.; Vonhoff, S.; Davies, J.; Teh, M-T.; Sugden, D. Mapping the melatonin receptor. 5. Melatonin agonists and antagonists derived from tetrahydrocyclopent [b]indoles, tetrahydrocarbazoles and hexahydrocyclohept [b]indoles. J. Med. Chem. 1998, 41, 451-467.
90. Spadoni, G.; Balsamini, C.; Diamantini, G.; Di Giacomo, B.; Tarzia, G.; Mor, M.; Plazzi, P. V.; Rivara, S.; Lucini, V.; Nonno, R.; Pannacci, M.; Fraschini, F.; Stankov, B. M. Conformationally restrained melatonin analogs: Synthesis, binding affinny for the melatonin receptor, evaluation of the biological activity, and molecular modeling study. J. Med. Chem. 1997, 40, 1990-2002.
91. Sugden, D.; Yeh, L.-K.; Teh, M.-T. Design of subtype selective melatonin receptor agonists and antagonists. Reprod. Nutr. Dev. 1999, 39, 335-344.
92. Faust R.; Garratt, P. J.; Jones, R.; Yeh, L.-K.; Tsotinis, A.; Panoussopoulou, M.; Calogeropoulou, T.; Teh, M.-T.; Sugden, D. Mapping the melatonin receptor. 6. Melatonin agonists and antagonists derived from 6H-isoindolo[2,1-α]indoles, 5,6-dihydroindolo2,1-αi]isoquinolines, and 6,7-dihydro-5H-benzo[c]azepino[2,1 -α]indoles. J. Med. Chem. 2000, 43, 1050-1061.
93. Yous, S.; Andrieux, J.; Howell, H, E.; Morgan, P.; Renard, P.; Pfeiffer, B.; Lesieur, D.; Guardiola-Lemaitre, B. Novel naphthalenic ligands with high affinity for the melatonin receptors. J. Med. Chem. 1992, 35, 1484-1486.
94. Dubocovich, M. L. Drug evaluation: Agomelatine targets a range of major depressive disorders symptoms. Curr. Opin. Invest. Drugs 2006, 7, 670-680.
95. Leclerc, V.; Depreux, P.; Lesieur, D.; Caignard, D. H.; Renard, P.; Delagrange, P.; Guardiola-Lemaitre, B.; Morgan, P. Synthesis and biological activity of conformationally restricted tricyclic analogs of the hormone melatonin. Bioorg. Med. Chem. Lett. 1996, 6, 1071-1076.
96. Mathé-Allainmat, M.; Le Gall, M.; Jellimann, C.; Andrieux, J.; Langlois, M. Synthesis of β-substituted naphth-1-yl ethylamido derivatives as new melatoninergic agonists. Bioorg. Med. Chem. 1999, 7, 2945-2952.
97. Li, P.-K.; Chu, G.-H.; Gillen, M. L., Parekh, T.; Witt-Enderby, P. A. The development of a charged melatonin receptor ligand. Bioorg. Med. Chem. Lett. 1997, 7, 2409-2414.
98. 125I]iodomelatonin binding sites. J. Med. Chem. 1995, 38, 2050-2060.
99. Li, P.-K.; Chu, G.-H.; Gillen, M. L.; Witt-Enderby, P. A. Synthesis and receptor binding studies of quinolinic derivatives as melatonin receptor ligands. Bioorg. Med. Chem. Lett. 1997, 7, 2177-2180.
100. Fourmaintraux, E.; Depreux, P.; Lesieur, D.; Guardiola-Lemaêtre, B.; Bernnejean, C.; Delagrange, P.; Howell, H. Tetrahydronaphthalenic derivatives as new agonist and antagonist ligands for melatonin receptors. Bioorg. Med. Chem. 1998, 6, 9-13.
101. Garratt, P. J., Travard, S.; Vonhoff, S.; Tsotinis, A.; Sugden, D. Mapping the melatonin receptor. 4. Comparison of the binding affinities of a series of substituted phenylalkyl amides. J. Med. Chem. 1996, 39, 1797-1805.
102. Jellimann, C.; Mathé-Allainmat, M.; Andrieux, J.; Kloubert, S.; Boutin, J. A.; Nicolas,, J. P.; Bennejean, C.; Delagrange, P.; Langlois, M. Synthesis of phenalene and acenaphthene derivatives as new conformationally restricted ligands for melatonin receptors. J. Med Chem. 2000, 43, 4051-4062.
103. Math-Allainmat, M.; Gaudy, F.; Sicsic, S.; Dangy-Caye, A.-L.; Shen, S.; Bremont, B.; Benatalah, Z.; Langlois, M.; Renard, P.; Delagrange, P. Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors. J. Med. Chem. 1996, 39, 3089-3095.
104. Jellimann, C.; Mathé-Allainmat, M.; Andrieux, J.; Renard, P.; Delagrange, P.; Langlois, M. Melatonergic properties of the (+)- and (-)-enantiomers of N-(4-methoxy-2,3-dihydro-1H-phenalen-2- y1)amide derivatives. J. Med. Chem. 1999, 42, 1100-1105.
105. Copinga, S.; Tepper, P. G.; Grol, C. J.; Hom, A. S.; Dubocovich, M. L. 2-Amido-8-medioxytetralins: A series of nonindolic melatonin-like agents. J. Med. Chem. 1993, 36, 2891-2898.
106. Jansen, J. M.; Copinga, S.; Gruppen, G.; Molinari, E. J.; Dubocovich, M. L.; Grol, C. J. The high affinity melatonin binding site probed with conformationally restricted ligands-I. Pharmacophore and minireceptor models. Bioorg. Med. Chem. 1996, 4, 1321-1332.
107. Sugden, D. N-Acyl-3-amino-5-methoxychromans: A new series of non-indolic melatonin analogues. Eur. J. Pharmacol. 1994, 254, 271-275.
108. Marot C.; Chavatte, P.; Morin-Allory, L.; Viaud, M. C.; Guillaumet, G.; Renard, P.; Lesieur, D.; Michel, A. Pharmacophoric search and 3D-QSAR comparative molecular field analysis studies on agonists of melatonin sheep receptors. J. Med. Chem. 1998, 41, 4453-4465.
109. Sicsic, S.; Serraz, I.; Andrieux, J.; Brémont, B.; Mathé-Allainmat, M.; Poncet, A.; Shen, S.; Langlois, M. Three-dimensional quantitative structure-activity relationship of melatonin receptor ligands: A comparative molecular field analysis study. J. Med. Chem. 1997, 40, 739-748.
110. Mor, M.; Rivara, S.; Silva, C.; Bordi, F.; Plazzi, P. V.; Spadoni, G.; Diamantini, G.; Batsamini, C.; Tarzia, G.; Fraschini, F.; Lucini, V.; Nonno, R.; Stankov, B. M. Melatonin receptor ligands: Synthesis of new melatonin derivatives and comprehensive comparative molecular field analysis (CoMFA) study. J. Med. Chem. 1998, 41, 3831-3844.
111. Lucini, V.; Pannacci, M.; Scaglione, F.; Fraschini, F., Rivara, S.; Mor, M.; Bordi F.; Plazzi, P. V.; Spadoni, G.; Bedini, A.; Piersanti, G.; Diamantini G.; Tarzia, G. Tricyclic alkylamides as melatonin receptor ligands with antagonist or inverse agonist activity. J. Med. Chem. 2004, 47, 4202-4212.
112. 2-adrenergic G protein-coupled receptor. Science 2007, 318, 1258-1265.
113. 2-adrenergic receptor function. Science 2007, 318, 1266-1273.
114. 2 adrenergic G-protein-coupled receptor. Nature 2007, 450, 383-387.
115. Grol, C. J.; Jansen, J. M. The high affinity melatonin binding site probed with conformationally restricted ligands-II. Homology modeling of the receptor. Bioorg. Med. Chem. 19, 4, 1333-1339.
116. 2 melatonin receptor: The role of Va1204, Leu272 and Tyr298 in ligand binding. J. Neurochem. 2004, 91, 836-842.
117. Ivanov, A. A.; Voronkov, A. E.; Baskin, I. I.; Palyulin, V. A.; Zefirov, N. S. The study of the mechanism of binding of human ML1A melatonin receptor ligands using molecular modeling. Doklady Biochem. Biophys. 2004, 394, 49-52.
118. 2 receptor models. J. Med. Chem. 2005, 48, 4049-4060.
119. 2 melatonin receptor: The role of residues in transmembrane domains 3, 6, and 7. Biochem. Biophys. Res. Commun. 2005, 332, 726-734.
120. Voronkov, A. E.; Ivanov, A. A.; Baskin, I. I.; Palyulin, V. A.; Zefirov, N. S. Molecular modeling study of the mechanism of ligand binding to human melatonin receptors. Doklady Biochem. Biophys. 2005, 403, 284-288.
121. Chugunov, A. O.; Farce, A.; Chavatte, P.; Efremov, R. G. Differences in binding sites of two melatonin receptors help to explain their selectivity to some melatonin analogs: A molecular modeling study. J. Biomol. Struct. Dyn. 2006, 24, 91-107.
122. Fukatsu, K.; Uchikawa, O.; Kawada, M.; Yamano, T.; Yamashita, M.; Kato, K.; Hirai, K.; Hinuma, S.; Miyamoto, M.; Ohkawa, S. Synthesis of a novel series of benzocycloalkene derivatives as melatonin receptor agonists. J. Med. Chem. 2002, 45, 4212-4221.
123. Uchikawa, O.; Fukatsu, K.; Tokunoh, R.; Kawada, M.; Matsumoto, K.; Imai, Y.; Hmuma, S.; Kato, K.; Nishikawa, H.; Hirai, K.; Miyamoto, M.; Ohkawa, S. Synthesis of a novel series of tricyclic indan derivatives as melatonin receptor agonists. J. Med Chem. 2002, 45, 4222-4239.
124. Epperson, J. R.; Bruce, M. A.; Catt, J. D.; Deskus, J. A.; Hodges, D. B.; Karageorge, G. N.; Keavy, D. J.; Mahle, C. D.; Mattson, R. J.; Ortiz, A. A.; Parker, M. F.; Takaki, K.S.; Watson, B. T.; Yevich. J. P. Chronobiotic activity of N-[2-(2,7-dimethoxyfluoren-9-yl)ethyll-propanamide. Synthesis and melatonergic pharmacology of fluoren-9-ylethyl amides. Bioorg. Med. Chem. 2004, 12, 4601-4611.
125. Tsotinis, A.; Panoussopoulou, M.; Hough. K.; Sugden. D. Synthesis and biological evaluation of new β, β-disubstituted 6,7,8,9-tetrahydropyrido[1,2-α]indol-10-yl ethylamido melatoninergic ligands. Eur. J. Pharm. Sci. 2003, 18, 297-304.
126. 2 receptors. Naumyn-Schmiedeberg's Arch Pharmacol. 2003, 367, 553-561.
127. Charton, I.; Suzenet, F.; Boutin, J. A.; Audinot, V.; Delagrange, P.; Bennejean, C.; Renard, P.; Guillaumet G. Synthesis of 5-substituted-2,3-dihydro-1, 4-benzoxathiins: Biological evaluation as melatonin receptors ligands. J. Enzyme Inhib. Med. Chem. 2003, 18, 187-193.
128. Sun, L.-Q.; Chen, J.; Bruce, M.; Deskus, J. A.; Epperson, J. R.; Takaki, K.; Johnson, G.; Iben, L.; Mahle, C. D.; Ryan, E.; Xu, C. Synthesis and structure-activity relationship of novel benzoxazole derivatives as melatonin receptor agonists. Bioorg Med. Chem. Lett. 2004, 14, 3799-3802.
129. Sun, L.-Q.; Chen, J.; Takaki, K.; Johnson, G.; Iben, L.; Mahle, C. D.; Ryan, E.; Xu, C. Design and synthesis of benzoxazole derivatives as novel melatoninergic ligands. Bioorg. Med. Chem. Lett. 2004, 143, 1197-1200.
130. Sun, L.-Q.; Chen, J.; Mattson, R. J.; Epperson, J. R.; Deskus, J. A.; Li, W. S.; Takaki, K.; Hodges, D. B.; Iben, L.; Mahle, C. D.; Ortiz, A.; Molstad, D.; Ryan, E.; Yeleswaram, K.; Xu, C.; Luo, G. Heterocyclic aminopyrrolidine derivatives as melatoninergic agents. Bioorg. Med. Chem. Lett. 2003, 13, 4381-4384.
131. 2-selective melatonin receptor ligands. J. Med. Chem. 2006, 49, 7393-7403.
132. Rivara, S.; Lodola, A.; Mor, M.; Bedini, A.; Spadoni, G.; Lucini, V.; Pannacci, M.; Fraschini, F.; Scaglione, F.; Sanchez, R. O.; Gobbi, G.; Tarzia, G. N-(Substituted-anilinoethyl)amides: Design, synthesis, and pharmacological characterization of a new class of melatonin receptor ligands. J. Med. Chem. 2007, 50, 6618-6626.
133. Di Giacomo, B.; Bedini, A.; Spadoni, G.; Tarzia, G.; Fraschini, F.; Pannacci, M.; Lucini, V. Synthesis and biological activity of new melatonin dimeric derivatives. Bioorg. Med. Chem. 2007, 15, 4643-4650.
134. Rivara, S.; Diamantini, G.; Di Giacomo, B.; Lamba, D.; Gatti, G.; Lucini, V.; Pannacci, M.; Mor, M.; Spadoni, G.; Tarzia, G. 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.
135. 2 receptor agonists. Bioorg. Med. Chem. Lett. 2004, 14, 1023-1026.
136. 2 melatoninergic ligands. Bioorg. Med. Chem. 2003, 11, 753-759.
137. Gatti, G.; Piersanti G.; Spadoni, G. Conformation by NMR of two tetralin-based receptor ligands. Farmaco. 2003, 58, 469-476.
138. Sun, L.-Q.; Takaki, K.; Chen, J.; Iben, L.; Knipe, J. O., Pajor, L.; Mahle, C. D.; Ryan, E.; Xu, C. N-2-2-(4-Phenylbutyl)benzofuran-4-yl]cyclopropylmethyl]acetamide: an orally bioavailable melatonin receptor agonist. Bioorg. Med. Chem. Lett. 2004, 14, 5157-5160.
139. Sun, L.-Q.; Takaki, K.; Chen, J.; Bertenshaw, S.; Iben, L.; Mahle, C. D.; Ryan, E.; Wu, D.; Gao, Q.; Xu, C. (R)-2-(4-Phenylbutyl) dihydrobenzofuran derivatives as melatoninergic agents. Bioorg. Med. Chem. Lett. 2005, 15, 1345-1349.
140. 2-antagonist properties. J. Pineal Res. 2000, 29, 234-240.
141. Becker, J. R.; Thomas, S. Future treatment for depression, anxiety, sleep disorders, psychosis and ADHD. www.neurotrans mitter.net/ newdrugs.html
142. Fitzgerald, L. R.; Reed, J. E. Melatonin agonists for the treatment of sleep disorders and major depression. Ann. Rep. Med. Chem. 2004, 39, 25-37.
143. Palomer, A.; Princep, M.; Guglietta, A. Recent advances in the treatment of insomnia. Ann. Rep. Med. Chem. 2007, 42, 63-80.
144. Roth, T.; Stubbs, C.; Walsh, J. K. Ramelteon (TAK-375), a selective MT1/ MT2-receptor agonist, reduces latency to persistent sleep in a model of transient insomnia related to a novel sleep enviroment. Sleep 2005, 28, 303-307. Erratuin in Sleep, 2006, 29, 417 (dosage error in text).
145. Mini, L. J.; Wang-Weigand, S.; Zhang, J. Self-reported efficacy and tolerability of ramelteon 8 mg in older adults experiencing severe sleep-onset difficulty. Am. J. Geriatr. Pharmacother. 2007, 5, 177-184.
146. Karim, A.; Tolbert, D.; Cao, C. Disposition kinetics and tolerance of escalating single doses of ramelteon, a high-affinity MT1 and MT2 melatonin receptor agonist indicated for treatment of insomnia. J. Clin. Pharmacol. 2006, 46, 140-148.
147. Erman, M.; Seiden, D.; Zammit, G.; Sainati, S.; Zhang, J. An efficacy, safety, and dose-response study of Ramelteon in patients with chronic primary insomnia. Sleep Med. 2006, 7, 17-24.
148. 2 receptor agonist. Neuropharmacol. 2005, 48, 301-310.
149. http://www.drugs.com/ppa/ramelteon.html
150. 2C receptors, blockade of which enhances the activity of frontocortical dopaminergic and adrenergic pathways. J. Pharmacol. Exp. Ther. 2003, 306, 954-964.
151. Bourin, M.; Mocaer, E.; Porsolt, R. Antidepressant-like activity of S 20098 (agomelatine) in the forced swimming test in rodents: Involvement of melatonin and serotonin receptors. J. Psychiatry Neurosci. 2004, 29, 126-133.
152. Montgomery, S. A. Major depressive disorders: Clinical efficacy and tolerability of agomelatine, a new melatonergic agonist. Eur. Neuropsycopharmacol. 2006, 16, S633-39.
153. www.tikvahtherapeutics.com
154. Zemlan, F. K.; Mulchahey, J. J.; Scharf, M. B.; Mayleben, D. W.; Rosenberg, R.; Lankford, A. The efficacy and safety of the melatonin agonist β-methyl-6-chloromelatonin in primary insomnia: A randomized, placebo-controlled, crossover clinical trial. J. Clin. Psychiatry 2005, 66, 384-390.
155. Nickelsen, T.; Samel, A.; Vejvoda, M.; Wenzel, J.; Smith, B.; Gerzer, R. Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9H time shift: Results of a placebo-controlled trial. Chronobiol. Int. 2002, 19, 915-936.
156. http://www.vandapharma.com/development-vec162.html
157. Birznieks, G.; Scott, C,; Baroldi, P.; Polymeropoulos, M.; Roth, T. Melatonin agonist VEC-162 improves sleep onset and manteinance in a model of transient insomnia. SLEEP, 2007, Abstract 0773 in www.journalsleep.org/PDF/AbstractBook2007.pdf.
158. Naguib, M.; Baker, M. T.; Spadoni, G.; Gregerson, M. The hypnotic and analgesic effects of 2-bromomelatonin. Anesth. Analg. 2003, 97, 763-768.
159. Sanchez, R. O.; Karam, F.; Bambico, F. R.; Katz, N.; Spadoni, G.; Bedini, A.; Mor, M.; Rivara, S.; Fraschini, F.; Tarzia, G.; Gobbi, G. A novel melatonin partial agonist with sleep-promoting properties, ACNP 45th Annual Meeting, December 3-7, 2006; American College of Neuropsychopharmacology: Hollywood, FL, 2006; S157.
160. Sanchez, R. O.; Cohen, G.; Spadoni, G.; Bedini, A.; Mor, M.; Rivara, S.; Fraschini, F.; Tarzia, G.; Gobbi, G. Selective increase of Slow Wave Sleep (SWS) by a novel melatonin partial agonist. 37th Annual Meeting Neuroscience 2007, San Diego, CA, Nov 3-7, 2007; Poster 244.4/G16.
161. Karam, F.; Bambico, F. R.; Sanchez, R. O.; Katz, N.; Spadoni, G.; Bedini, A.; Mor, M.; Rivara, S.; Fraschini, F.; Tarzia, G.; Gobbi, G. A novel melatonin partial agonist with sleep-promoting properties and anti-anxiety effects. 36th Annual Meeting Neuroscience 2006, Atlanta, GA, Oct 14-18, 2006; Poster 830.21/GG11.