Therapeutic potential of melatonin receptor agonists and antagonists

Abstract

1. Summary In humans, the hormone melatonin is produced and secreted from the pineal gland following a circadian rhythm with high levels during the normal hours of sleep at night and low levels during the day. The strong correlation between the sleep-wake cycle and the sleep-promoting effects of physiological and pharmacological doses of melatonin has lead to the hypotheses that melatonin can be used to treat insomnia and circadian sleep disorders. Insomnia is associated with daytime sleepiness and decrements in mental and physical performance. In the last decade, efforts from a number of pharmaceutical companies have aimed to discover and develop high affinity melatonin receptor agonists. Melatonin receptor agonists currently in development for the treatment of sleep disorders are non-selective in that they activate multiple melatonin receptor subtypes. This review highlights the main pharmacological properties and clinical uses of these melatonin analogues, and provides an assessment of the therapeutic potential of subtype-selective melatonin receptor agonists and antagonists. The efficacy and effectiveness of melatonin receptor agonists should be greatly increased and the side-effects reduced by targeting receptor subtypes mediating specific functions. The current need for the synthesis and characterisation of high affinity and subtype-selective melatonin receptor antagonists to further elucidate the physiological role of melatonin is also discussed. The discovery of drugs for the treatment of sleep disorders which are devoid of side-effects and which have novel mechanisms of action, is of current