Melatonin Receptor Agonists: SAR and Applications to the Treatment of Sleep-Wake Disorders

Abstract

Melatonin (N-acetyl-5-methoxytryptamine) is synthesized and released by the pineal gland following a circadian rhythm characterized by high levels during the night. It shows several pharmacological effects on diverse cellular and animal models, mainly related to either its antioxidant activity or to its ability to activate specific receptors (MTr). Melatonin is widely used as a self-administered food additive, but its therapeutic potential needs more investigation and is hampered by its poor pharmacokinetics. This review will focus on the medicinal chemistry of agonist ligands of the two human GPCRs MT(1) and MT(2) melatonin receptors. The recent introduction of ramelteon, a non-selective MT(1)/MT(2) agonist for the treatment of insomnia, and the advancement to clinical trials of other MTr agonists have renewed interest for different classes of compounds endowed with this activity. Several chemical classes of MTr agonists are described in the literature, generally characterized by an indole, or an indole bioisostere, carrying an amide side chain and a methoxy group, or substituents with similar stereoelectronic features. Abundant information is available for non-selective MT(1)/MT(2) ligands, and several molecular models, both ligand- and receptor-based, have been proposed to rationalize their structure activity relationships. Fewer classes of selective agonists have been reported in the literature, and they could help clarifying the physiological role of the two receptor subtypes. A brief discussion on the therapeutic potential of this class of compounds is based on the clinical data available for the agonists ramelteon, agomelatine, beta-methyl-6-chloromelatonin (TIK-301) and VEC-162.

Hormones, hormonal agents, and neuropeptides involved in the neuroendocrine regulation of sleep in humans

“…120 Several clinical data are available for the melatonin agonists ramelteon, agomelatine, beta-methyl-6-chloromelatonin (TIK-301), and tasimelteon (VEC-162) in humans with regard to their contribution in the treatment of sleep-wake disorders. 121 Ramelteon, the first to be approved for the treatment of chronic insomnia, has been shown to enhance subjective sleep quality in some, but not all, studies, 122 especially in adults with generalized anxiety disorder, 123 and in menopausal women. 124 Agomelatine, which combines the properties of a 5-HT(2C) antagonist and a melatonergic MT(1)/MT(2) receptor agonist, has been found to be very effective in re-setting the disturbed sleep/wake cycle and in improving the clinical status of major depressive disorder (MDD).…”

N‐(Anilinoethyl)amides: Design and Synthesis of Metabolically Stable, Selective Melatonin Receptor Ligands

“…[18] These limitations have prompted evaluation of the hypnotic effect of synthetic melatonin receptor agonists (Figure 1), some of which appear to possess interesting efficacy. [19][20][21] These compounds combine the positive aspects of melatonin treatment, such as the absence of major changes in sleep architecture and day-after side effects, with a longer half-life. Ramelteon, for example, is a tricyclic MT 1 and MT 2 melatonin receptor agonist approved for the treatment of insomnia as characterized by difficulty in sleep onset.…”

Melatonin and Synthetic Melatonergic Agonists: Actions and Metabolism in the Central Nervous System

“…TIK-301 (21) has received an orphan drug designation by FDA for the treatment of sleep disorders in blind individuals. Its affinity to MT 1 receptors (pK i = 10.09) is similar to that of melatonin (1), but that to MT 2 substantially higher (pK i = 10.38) [282,305].…”

“…Therefore, only those drugs will be considered that are either approved by agencies such as FDA or EMEA, have been clinically studied or are of interest because of particular, unusual properties. These compounds have been repeatedly reviewed, also on a comparative basis [14,17,37,85,153,[282][283][284][285][286][287][288][289][290][291][292]. Instead of repeating here the whole body of clinical findings, we shall focus on the properties of the drugs.…”