Melatonergic Treatment: Focus on Metabolism andChronobiology

Introduction: Melatonin is produced in various organs, but its preferentially nocturnalsynthesis and release by the pineal gland is decisive for its chronobiological actions.The short half-life of circulating melatonin has been reason for developing syntheticmelatonergic agonists. With regard to age- and disease-related dysfunction of themelatonergic system, treatment with melatonin or its synthetic analogs may be used foralleviating health problems with a respective etiology. This review addresses limitationsarising from drug-specific metabolism and disregarded chronobiological rules.Metabolism: Differences are illustrated by comparing the metabolism of melatonin andtwo approved synthetic melatonergic agonists, ramelteon and agomelatine. Apart fromhydroxylation and dealkylation reactions, melatonin can be converted to methoxylatedkynuramines, a route absent in the two synthetic drugs. An unsual property is present inthe ramelteon metabolite M-II, which still displays melatonergic activity, but attains 30 to100 times higher levels than the parent compound. Two double-hydroxylated agomelatinemetabolites may be involved in sometimes occurring hepatotoxicity.Chronobiology of Melatonergic Drugs: Sleep latency facilitation and readjustmentof circadian rhythms require only short actions. Circadian entrainment must considerthe phase response curve and requires repetitive well-timed administration. Findingsin nocturnally active rodents cannot be generally translated to humans, especially notregarding sleep and, perhaps, not in insulin resistance.Conclusions: Melatonin and synthetic analogs can be suitable for treating sleep-onsetdifficulties, circadian rhythm sleep disorders and subtypes of depression with an etiologyof circadian dysfunction. Applications in the field of metabolic syndrome and insulinresistance have to be seen with caution

کلیدواژه ها:

AgomelatineCircadianMelatoninKynuramineRamelteon