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.

Neuroprotective mechanism of the novel melatonin derivative Neu-P11 in brain ischemia related models

“…However, several authors have proposed the need of developing new compounds or prolonged-release preparations of melatonin or new melatonin agonists with a longer duration (14,55). In this respect, different melatonin derivatives are being investigated, for example, ramelteon (it has 3-16 times higher affinity for MT receptors compared to melatonin), agomelatine, (melatonergic compound with antidepressant properties), tasimelteon or TIK-301, among others (14,56,57).…”

Publication analysis on insomnia: how much has been done in the past two decades?

“…The orexin system mainly promotes arousal; orexin antagonists have the potential to selectively promote sleep [27][28][29][30] and have fewer side effects [22]. Melatonin agonist drugs (eg, melatonin [31][32][33][34][35], ramelteon [36][37][38][39][40]) and antihistamine drugs (eg, diphenhydramine) [27][28][29][30] have also been studied extensively in recent years [41].…”

Agomelatine, melatonin and depressive disorder

“…This is reinforced by the therapeutic utility of medications acting as melatonin agonists. Neither of the two licenced melatonin agonists, ramelton or tasimelton, appear to have antidepressant actions [24]. Similarly, melatonin itself has little or no antidepressant effects.…”

“…In major depression, light therapy may be useful as an adjunct to conventional antidepressant agents, but has rarely been investigated as therapy alone. The more recent discovery of selective agonists at MT2 receptors has so far, in pre-clinical evaluations at least, demonstrated only anxiolytic actions [24]. Along with selective MT1 agonists, further pharmacological evaluation in relevant pre-clinical models is awaited in order to assess their antidepressant potential.…”