The circadian nature of melatonin secretion, coupled with the localization of melatonin receptors to the suprachiasmatic nucleus, has led to numerous studies of the role of melatonin 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 melatonin and its mechanisms of action, three therapeutic agents (ramelteon, prolonged-release melatonin, and agomelatine) are already in use, and melatonin receptor agonists are now appearing as new promising treatment options for sleep and circadian-rhythm related disorders.
Recently, Spadoni et al reviewed the medicinal chemistry strategies leading to MLT receptor agonists, and the evidence supporting therapeutic efficacy of compounds undergoing clinical evaluation.
A wide range of clinical trials demonstrated that ramelteon, prolonged-release melatonin 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.
Despite a large number of high affinity nonselective melatonin receptor agonists, only limited data on MT(1) or MT(2) subtype-selective compounds are available up to now. Administration of the MT(2)-selective agonist IIK7 to rats has proved to decrease NREM sleep onset latency, suggesting that MT(2) receptor subtype is involved in the acute sleep-promoting action of melatonin; rigorous clinical studies are needed to demonstrate this hypothesis. Further clinical candidates based on selective activation of MT(1) or MT(2) receptors are expected in coming years.