Therapeutic potential of melatonin agonists

Abstract

Melatonin, a hormone secreted by the pineal gland, has been successfully employed to improve sleep in both normal patients and insomniacs, and for the treatment of circadian rhythm sleep disorders. Melatonergic MT₁ and MT₂ receptors exist in high concentrations in the suprachiasmatic nucleus of the hypothalamus and have been shown to be instrumental for the sleep-promoting and circadian rhythm-regulating effects of melatonin. A lack of consistency among reports on the therapeutic efficacy of melatonin has been attributed to differences in melatonin's bioavailability and the short half-life of the hormone. In view of the need for longer acting melatonergic agonists that improve sleep efficiency without causing drug abuse or dependency, ramelteon (Rozerem™, Takeda) was developed. Ramelteon, which acts via MT₁/MT₂ melatonergic agonism, has been found clinically effective for improving total sleep time and sleep efficiency in insomniacs. Agomelatine (Valdoxan™, Servier) is another MT₁/MT₂ melatonergic agonist that also displays antagonist activity at 5-HT_2C serotonin receptors. Agomelatine has been found effective in treating depression and sleep disorders in patients with major depressive disorder. A slow-release preparation of melatonin (Circadin™, Neurim) has been shown to be effective in treating sleep disorders in the elderly population.

Keywords: Circadin; agomelatine; antidepressant; insomnia; major depressive disorder; melatonin; melatonin receptors; ramelteon.