Melatonin receptor

Melatonin [73-31-4] C 2H N202 (31) has marked effects on circadian rhythm (11). Novel ligands for melatonin receptors such as (32) (12), C2yH2gN202, have affinities in the range of 10 Af, and have potential use as therapeutic agents in the treatment of the sleep disorders associated with jet lag. Such agents may also be usehil in the treatment of seasonal affective disorder (SAD), the depression associated with the winter months. Histamine (see Histamine and histamine antagonists), adenosine (see Nucleic acids), and neuropeptides such as corticotropin-like intermediate lobe peptide (CLIP) and vasoactive intestinal polypeptide (VIP) have also been reported to have sedative—hypnotic activities (7). 

Melatonin produces its effects via the GPCR, ML-1. A second lower affinity form, ML-2, has been described on the basis of binding data. Activation of melatonin receptors can inhibit DA release in the retina. 

Figure 22.3 Possible links in the induction of circadian rhythm between daylight, the suprachiasmatic nucleus and melatonin release from the pineal gland. Some fibres in the optic nerve, projecting from the eye to the lateral geniculate nucleus (LGN) in the thalamus, innervate the suprachiasmatic nucleus (SCN) in the anterior hypothalamus, via the retinohypothalamic tract (RHT). Others project to the SCN from the LGN in the geniculohypothalamic tract (GHT). The release of melatonin into the circulation from the pineal gland (PG) is maximal at night and appears to be controlled partly by noradrenaline released from sympathetic nerves originating in the superior cervical ganglion (SCG). Melatonin receptors are found in the SCN, the removal of which dampens melatonin secretion...

Antihistamines such as diphenhydramine are known for their sedating properties and are frequently used over-the-counter medications (usual doses 25-50 mg) for difficulty sleeping. Diphenhydramine is approved by the FDA for the treatment of insomnia and can be effective at reducing sleep latency and increasing sleep time.43 However, diphenhydramine produces undesirable anticholinergic effects and carryover sedation that limit its use. As with TCAs and BZDRAs, diphenhydramine should be used with caution in the elderly. Valerian root is an herbal sleep remedy that has inconsistent effects on sleep but may reduce sleep latency and efficiency at commonly used doses of 400 to 900 mg valerian extract. Ramelteon, a new melatonin receptor agonist, is indicated for insomnia characterized by difficulty with sleep onset. The recommended dose is 8 mg at bedtime. Ramelteon is not a controlled substance and thus may be a viable option for patients with a history of substance abuse. 

Ribelayga C., Wang Y., Mangel S. (2004). A circadian clock in the fish retina regulates dopamine release via activation of melatonin receptors. J. Physiol. 554(2),... 

Melatonin receptor agonists in the treatment of sleep disorders... 

LY 156735 is a [1-substituted analog of melatonin that has greater bioavailability than melatonin (Nickelsen et al. 2002). It is in an earlier stage of clinical trials in initial trials, it reduced the sleep onset time in patients with moderate sleep-onset insomnia. Several other specific melatonin receptor agonists and antagonists are in development (Rivara et al. 2005 Zlotos 2005) and presumably will be clinically tested over the next few years. 

Al-Ghoul, W. M., Herman, M. D. Dubocovich, M. L. (1998). Melatonin receptor subtype expression in human cerebellum. Neuroreport 9, 4063-8. 

Brydon, L., Petit, L., Delagrange, P., Strosberg, A. D. Jockers, R. (2001). Functional expression of mt2 (mellb) melatonin receptors in human paz6 adipocytes. Endocrinology 142, 4264-71. 

Cardinah, D. P. Vacas, M. I. (1980), Molecular endocrinology of melatonin Receptor sites in brain and peripheral organs. Adv. Biosci. 29, 237-46. 

Gall, C. von, Stehle, J. H. Weaver, D. R. (2002). Mammalian melatonin receptors molecular biology and signal transduction. Cell Tiss. Res. 309, 151-62. 

Gauer, F Masson-Pevet, M. Pevet, P. (1993). Melatonin receptor density is regulated in rat pars tuberalis and suprachiasmatic nuclei by melatonin itself. Brain Res. 602, 153-6. 

Prolonged exposure to melatonin leads to time-dependent sensitization of adenylate cyclase and down-regulates melatonin receptors in pars tuberalis cells from ovine pituitary. Endocrinology 132, 285-92. 

MacKenzie, R. S., Melan, M. A., Passey, D. K. Witt-Enderby, P. A. (2002). Dual coupling of MTi and MT2 melatonin receptors to cyclic AMP and phosphoinositide signal transduction cascades and their regulation following melatonin exposure. Biochem. Pharmacol. 63, 587-95. 

Masana, M. I., Soares, J. M. Jr Dubocovich, M. L. (2005). 17beta-Estradiol modulates hMT(l) melatonin receptor function. Neuroendocrinology 81, 87-95. 

Mazzucchelli, C Pannacci, M., Nonno, R. et al. (1996). The melatonin receptor in the human brain cloning experiments and distribution studies. Brain Res. Mol. 

Nelson, C. S., Marino, J. L. Allen, C. N. (1996). Melatonin receptors activate heteromeric G-protein coupled Kir3 channels. Neuroreport 7, 717-20. 

Reppert, S. M., Godson, C., Mahle, C. D. et al. (1995). Molecular characterization of a second melatonin receptor expressed in human retina and brain the Mein, melatonin receptor. Proc. Natl. Acad. Sci USA 92, 8734-8. 

Reppert, S. M., Weaver, D. R. 8r Ebisawa, T. (1994). Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 13, 1177-85. 

Roy, D. Belsham, D. D. (2002). Melatonin receptor activation regulates GnRH gene expression and secretion in GT1-7 GnRH neurons. Signal transduction mechanisms. J. Biol. Chem. 277, 251-8. 

Tenn, C. Niles, L. P. (1993). Physiological regulation of melatonin receptors in rat suprachiasmatic nuclei diurnal rhythmicity and effects of stress. Mol. Cell. Endocrinol. 98, 43-8. 

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