Melatonin (N-acetyl-5-methoxytryptamine, MLT) is a neurohormone, primarily secreted at night in all species by the pineal gland (Barrenetxe, J.; Delagrange, P.; Martinez, J. A. J. Physiol. and Biochem. 2004, 60, 61-72).
The circadian pattern of MLT secretion, coupled with the localization of specific MLT binding sites in the brain region associated with the “biological clock”, suggests that MLT may play an important role in modulation of the sleep-wake cycle and circadian rhythms in humans (Pevet, P.; Bothorel, B.; Slotten, H.; Saboureau, M. Cell Tissue Res. 2002, 309, 183).
There is evidence that the administration of MLT is of clinical utility in the treatment of various conditions including jet-lag, work-shift syndrome, sleep disorders, glaucoma, reproduction, cancer, immune disorders, obesity, eating disorders, and other neuroendocrine disorders, neurodegenerative disorders, cardiovascular diseases, neuropsychiatric diseases such as depression, anxiety, Alzheimer's disease, Parkinson's disease and other motor related diseases, autism, attention deficit hyperactivity disorder and some inflammatory diseases such as rheumatoid arthritis.
The chronobiotic properties of MLT are of particular interest since the disorganization of internal rhythms is believed to be involved in the pathophysiology of depression. Melatonin was suggested as having therapeutic benefits for individuals suffering from depression (Halbreich, U. Psychopharmacol. Bull. 1997, 33, 281-286; Eison, A. S.; Freeman, R. P.; Guss, V. B., Mullins, U. L.; Wright, R. N. J. Pharmacol. Exp. Ther. 1995, 273, 304-308; Brotto, L. A.; Barr, A. M.; Gorzalka, B. B. Eur. J. Pharmacol. 2000, 402, 87-93). Moreover, some melatonin agonists having improved properties in comparison to melatonin are now in clinical trials for the treatment of depression, insomnia or circadian rhythm sleep disorders (Loo, H.; Hale, A.; D'haenen, H. Int. Clin. Psychopharmacol. 2002, 17, 239-47; Turek, F. W; Gillette, M. U. Sleep Med. 2004, 5, 523-32; Chilman-Blair, K.; Castaner, J.; Bayes, M.; Silvestre, J. S.; Bayes, M. Drug Future 2003, 28, 950; Zemlan, F. P.; Mulchahey, J. J.; Scharf, M. B.; Mayleben, D. W.; Rosenberg, R.; Lankford, A. J. Clinic. Psychiatry 2005, 66, 384-390). Furthermore, the treatment of stressed mice with MLT was shown to reverse some stress-induced behavioral disturbances (Kopp, C.; Vogel, E.; Rettori, M.-C.; Delagrange, P.; Misslin, R. Behaviour Pharmacol. 1999, 10, 73).
Most of the physiological effects of MLT result from the activation of high-affinity G-protein coupled receptors, two of which (MT1 and MT2) have been found in mammals including humans and which have been subsequently cloned (Reppert, S. M.; Weaver, D. R.; Goodson, C. Trends Pharmacol. Sci. 1996, 17, 100; 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; Von Gall, C.; Stehle, J. H.; Weaver, D. R. Cell Tissue Res. 2002, 309, 151). A third subtype (Mel1c), first cloned from Xenopus laevis, has been found in non-mammalians only.
In addition to these high-affinity MLT receptors (Ki≅0.1 nM), another low-affinity MLT binding site, termed MT3 (Ki≅60 nM), has recently been characterized as a melatonin-sensitive form of the human enzyme quinone reductase 2 (Nosjean O., Ferro M., Cogé F., Beauverger P., Henlin J.-M., Lefoulon F., Fauchére J.-L., Delagrange P., Canet E., Boutin J. A. J. Biol. Chem. 2000, 275, 31311).
Other effects of MLT described in the literature include its neuroprotective (Liu, R. Y.; Zhou, J. N.; van Heerikhuize, J; Hofman, M. A.; Swaab, D. F. J. Clin. Endocrinol. Metab. 1999, 84, 323-327; Zisapel, N. Cellular and Molecular Neurobiology 2001, 21, 605-14; Kondoh, T.; Uneyama, H.; Nishino, H.; Torii, K. Life Sci. 2002, 72, 583-90), anti-inflammatory (Genovese, T.; Mazzon, E.; Muia, C.; Bramanti, P.; De Sarro, A.; Cuzzocrea, S. J. Pineal Res. 2005, 38, 198-208; Maestroni, G. J. M.; Sulli, A.; Pizzorni, C.; Villaggio, B.; Cutolo, M. Ann. N.Y. Acad. Sci. 2002, 966, 271-275), pain modulatory (Peres, M. F. Cephalalgia. 2005, 25, 403-11), retinal (Iuvone, P. M.; Tosini, G.; Pozdeyev, N.; Hague, R.; Klein, D. C.; Chaurasia, S. S. Progress in Retinal and Eye Research 2005, 24, 433-456), vascular (Sewerynek, E. Neuroendocrinology Letters 2002, 23 (Suppl. 1), 79-83; Doolen, S.; Krause, D. N.; Dubocovich, M. L.; Duckles, S. P. Eur. J. Pharmacol. 1998, 345, 67-69; Cagnacci, A.; Arangino, S.; Angiolucci, M.; Maschio, E.; Longu, G.; Melis, G. B. J. Pineal Res. 1997, 22, 16-19), antitumor ((a) Blask, D. E.; Sauer, L. A.; Dauchy, R. T. Curr. Topics in Med. Chem. 2002, 2, 113-132; (b) Sauer, L. A.; Dauchy, R. T.; Blask, D. E. Life Sci. 2001, 68, 2835-2844; (c) Collins, A.; Yuan, L.; Kiefer, T. L.; Cheng, Q.; Lai, L.; Hill, S. M. Cancer Lett. 2003, 189, 49-57), and antioxidant (Sofic, E.; Rimpapa, Z.; Kundurovic, Z.; Sapcanin, A.; Tahirovic, I.; Rustembegovic, A.; Cao, G. J. Neural Transmission 2005, 112, 349-358) properties.
Finally, a significant increase in the serum melatonin mean level could be observed in severely obese women (Shafii, M; MacMillan, D. R.; Key, M. P.; Kaufman, N.; Nahinsky, I. D. J. Am. Acad. Child Adolesc. Psychiatry 1997, 36, 412-6) suggesting a possible use of melatonin ligands in the treatment of obesity (Bylesjo, E. I.; Boman, K.; Wetterberg, L. Int. J. Eat Disord. 1996, 20, 443-46).
The specification refers to a number of documents, the contents of which is herein incorporated by reference in their entirety.