Focus on Metabolism and Chronobiology
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Focus Sci. Review Article Feb 2016, Volume 2, Issue 1 Melatonergic Treatment: Focus on Metabolism and Chronobiology Rüdiger Hardeland 1, * 1 Johann Friedrich Blumenbach Institute of Zoology and Anthropology, University of Göttingen, Göttingen, Germany * Corresponding author: Johann Friedrich Blumenbach Institute of Zoology and An- thropology, University of Göttingen, Berliner Str. 28, D-37073 Göttingen, Germany. Tel: +49-551395414. E-mail: [email protected] Submitted: 01.10.2016 Abstract Accepted: 02.12.2016 Introduction: Melatonin is produced in various organs, but its preferentially nocturnal synthesis and release by the pineal gland is decisive for its chronobiological actions. Keywords: The short half-life of circulating melatonin has been reason for developing synthetic Agomelatine melatonergic agonists. With regard to age- and disease-related dysfunction of the Circadian melatonergic system, treatment with melatonin or its synthetic analogs may be used for Melatonin alleviating health problems with a respective etiology. This review addresses limitations Kynuramine arising from drug-specific metabolism and disregarded chronobiological rules. Ramelteon Metabolism: Differences are illustrated by comparing the metabolism of melatonin and two approved synthetic melatonergic agonists, ramelteon and agomelatine. Apart from © 2016. Focus on Sciences hydroxylation and dealkylation reactions, melatonin can be converted to methoxylated kynuramines, a route absent in the two synthetic drugs. An unsual property is present in the ramelteon metabolite M-II, which still displays melatonergic activity, but attains 30 to 100 times higher levels than the parent compound. Two double-hydroxylated agomelatine metabolites may be involved in sometimes occurring hepatotoxicity. Chronobiology of Melatonergic Drugs: Sleep latency facilitation and readjustment of circadian rhythms require only short actions. Circadian entrainment must consider the phase response curve and requires repetitive well-timed administration. Findings in nocturnally active rodents cannot be generally translated to humans, especially not regarding sleep and, perhaps, not in insulin resistance. Conclusions: Melatonin and synthetic analogs can be suitable for treating sleep-onset difficulties, circadian rhythm sleep disorders and subtypes of depression with an etiology of circadian dysfunction. Applications in the field of metabolic syndrome and insulin resistance have to be seen with caution. INTRODUCTION secreted by the pineal gland is privileged as a circadian regula- tor. From this gland, the hormone is not only released to the Melatonin (N-acetyl-5-methoxytryptamine) has become circulation, but also, via the pineal recess, in even higher con- known as the hormone of the pineal gland, a role that is asso- centrations directly into the third ventricle of the brain [10]. ciated with the transmission of the signal ‘darkness’ [1], with In mammals, melatonin acts mainly via two membrane-bound, regulation of circadian rhythms at both central and peripheral G protein-coupled receptors, MT1 [11] and MT2 [12], encod- oscillators [2, 3], and, in diurnally active vertebrates including ed by the genes MTNR1A and MTNR1B, respectively. Anoth- the human, with sleep promotion [4, 5]. This is based on a er binding site that was previously believed to represent a third high-amplitude circadian rhythm of melatonin synthesis and melatonin receptor and had been provisionally denominated release with a prominent nocturnal peak. Regulation mecha- as “MT3”, has turned out to be an enzyme, quinone reductase nisms of melatonin biosynthesis have been described in detail 2 (= QR2 = NRH: quinone oxidoreductase 2 = NQO2) [13], [6, 7]. Melatonin is also synthesized in numerous extrapineal for which no signal transduction mechanism has been identi- sites and its total amounts in peripheral organs, especially the fied and which, therefore, cannot be categorized as a receptor. gastrointestinal tract (GIT), exceed the pineal levels by about Regulation mechanisms of signal transduction by MT1 and 400 – 500-fold [2, 7, 8]. This fact is frequently overlooked, but MT2, including receptor interactions with other proteins, and not of particular chronobiological relevance, because extrapi- discussion of further binding sites are reviewed elsewhere neal sites usually contribute poorly to the circulating levels and [14]. Doubts exist concerning retinoid-related orphan recep- exert only minor effects in the circadian system [9]. Except for tors (ROR/RZR), which have been considered as nuclear the retina, amplitudes of extrapineal melatonin rhythms are melatonin receptors and on which a considerable amount of usually low [2, 7]. Thus, in chronobiological terms, melatonin literature exists in the melatonin field. At least, the frequently Rüdiger Hardeland investigated RORα was recently reported to not possess rele- bution within the body. Moreover, with regard to melatonin vant affinity to melatonin [15], contrary to ealier belief. as well as its synthetic analogs, particular attention is neces- Several reasons exist for assuming that the maintenance of sary concerning chronobiological effects, which require a melatonin rhythmicity with high nocturnal levels are import- thorough understanding of the circadian system and its prop- ant to human health [2, 3, 16-18]. In brief, this judgment is erties to warrant a successful application. The aim of this re- based on evidence concerning the decline of melatonin lev- view is to direct the attention to (i) the profound differences els in the course of aging, the even more profound decrease in metabolism of melatonergic agonists, with regard to their observed in several neurodegenerative diseases, the reduction consequences to duration of action, formation of bioactive of melatonin concentrations in numerous other diseases and metabolites and adverse effects, as well as (ii) the necessity disorders, from metabolic syndrome, diabetes type 2, to vari- of understanding fundamental chronobiological issues, such ous neurological and mood disorders, and deviations in mel- as conditions requiring short or long actions, circadian phase atonergic signaling because of polymorphisms of melatonin dependence of efficacy, and limits of translating findings ob- receptors and biosynthetic enzymes. tained in nocturnally active rodents to the human. Melatonergic dysfunction, for whichever of these reasons, has numerous consequences, which are not at all surprising with MELATONERGIC AGONISTS AND THEIR DE regard to the pleiotropic, orchestrating role of the pineal hor- VIATIONS IN METABOLISM mone [2]. From a medical point of view, the following areas have become of particular interest: (i) readjustment of devi- An indolic moiety, as present in melatonin (Fig. 1), is not a ating circadian rhythms, in the context of circadian rhythm prerequisite for efficiently binding to 1MT and MT2 recep- sleep disorders (CRSDs) such as delayed sleep phase syn- tors. Only a few clinically studied agonists share this struc- drome (DSPS) and familial advanced sleep phase syndrome tural similarity with melatonin, in particular, TIK-301 (= (FASPS), in mood disorders with an etiology of circadian dys- β-methyl-6-chloromelatonin) and piromelatine [= Neu-P11= function such as forms of seasonal affective disorder (SAD) N-(2-(5-methoxy-1H-indol-3-yl)ethyl)-4-oxo-4H-pyran-2- and bipolar disorder (BP), in blindness and other cases of carboxamide, a melatonin analog in which the N-acetyl group poor entrainment by light/dark cycles or social synchroniz- is replaced by an oxopyran carboxyl structure]. Details and ers; (ii) other forms of depression, however, with limited justi- characteristics of further agonists have been recently summa- fication when aiming treatment at an exclusively melatonergic rized [22]. Various other core structures have been used in the basis; (iii) sleep promotion; (iv) avoidance and counteraction design of melatonergic agonists, such as indoline, indane, te- of metabolic dysregulation, especially with regard to the com- tralin, naphthalene, tetrahydroquinoline, anilinoethylamide, plex of metabolic syndrome, obesity, diabetes type 2 and insu- dihydrobenzofuranyl-cyclopropane and even diphenylamine lin resistance in the brain [4, 5, 16-18]. moieties [22-24]. Although these other structures allow high For purposes of a substitution therapy for individuals with affinities to the membrane-bound melatonin receptors and are decreased pineal function because of age or disease, mela- sometimes of great experimental value in terms of selectivity, tonin has a specific disadvantage. Its half-life in the circulation they are cause of profound differences in agonist metabolism. is remarkably short, usually ranging between 20 and 30 min, This shall be illustrated by comparing the catabolic pathways in the extremes between 10 and 45 min [16, 19]. In princi- of melatonin and two examples of clinically approved drugs, ple, there are two possible solutions to this problem, the use ramelteon and agomelatine (Fig. 1). Melatonin is primarily of controlled-release formulations of melatonin and the de- eliminated by cytochrome P450 (CYP) subforms, mainly via velopment of synthetic melatonergic agonists. Melatonin is 6-hydroxylation, to a smaller extent by demethylation [16]. generally highly tolerable, nontoxic [20] and may become 6-Hydroxymelatonin is conjugated and predominantly excret- critical only under specific conditions such as rheumatic dis- ed as 6-sulfatoxymelatonin. This route is responsible for the