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Review
. 2011 Dec;17(6):733-41.
doi: 10.1111/j.1755-5949.2010.00197.x.

Melatonin receptor agonists: new options for insomnia and depression treatment

Gilberto Spadoni  1 , Annalida Bedini, Silvia Rivara, Marco Mor
Affiliations
Review

Melatonin receptor agonists: new options for insomnia and depression treatment

Gilberto Spadoni et al. CNS Neurosci Ther. 2011 Dec.

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.

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Conflict of interest statement

The authors have no conflict of interest.

Figures

Figure 1
Figure 1
Melatonin (MLT) and clinically advanced MLT receptor agonists.
Figure 2
Figure 2
Strategies leading to melatonin receptor agonists.
Figure 3
Figure 3
Subtype‐ or functionally selective melatonin receptor agonists or partial agonists.
See this image and copyright information in PMC

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