title: Melatonin receptor agonists: new options for insomnia and depression treatment.
abstract: The circadian nature of melatonin (MLT) secretion, coupled with the localization of MLT receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of MLT in modulation of the sleep-wake cycle and circadian rhythms in humans. Although much more needs to be understood about the various functions exerted by MLT and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release MLT, and agomelatine) are already in use, and MLT receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders. In this review, emphasis has been placed on medicinal chemistry strategies leading to MLT receptor agonists, and on the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation. A wide range of clinical trials demonstrated that ramelteon, prolonged-release MLT and tasimelteon have sleep-promoting effects, providing an important treatment option for insomnia and transient insomnia, even if the improvements of sleep maintenance appear moderate. Well-documented effects of agomelatine suggest that this MLT agonist offers an attractive alternative for the treatment of depression, combining efficacy with a favorable side effect profile. Despite a large number of high affinity nonselective MLT receptor agonists, only limited data on MT₁ or MT₂ subtype-selective compounds are available up to now. Administration of the MT₂-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT₂ receptor subtype is involved in the acute sleep-promoting action of MLT; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT₁ or MT₂ receptors are expected in coming years.
authors.affiliation: Dipartimento di Scienze del Farmaco e della Salute, University of Urbino Carlo Bo, Urbino (PU), Italy. gilberto.spadoni@uniurb.it
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
mesh_terms: D000818:Animals; D003866:Depressive Disorder / Q000188:drug therapy*; D003865:Major Depressive Disorder / Q000188:drug therapy; D015195:Drug Design; D006801:Humans; D008550:Melatonin / Q000502:physiology; D044094:Receptors, Melatonin / Q000819:agonists*; D007319:Sleep Initiation and Maintenance Disorders / Q000188:drug therapy*; D013379:Substrate Specificity
chemical_list: D044094:Receptors, Melatonin; D008550:Melatonin