The melanin-concentrating hormone system as a target for the treatment of sleep disorders

Abstract

Given the widespread prevalence of sleep disorders and their impacts on health, it is critical that researchers continue to identify and evaluate novel avenues of treatment. Recently the melanin-concentrating hormone (MCH) system has attracted commercial and scientific interest as a potential target of pharmacotherapy for sleep disorders. This interest emerges from basic scientific research demonstrating a role for MCH in regulating sleep, and particularly REM sleep. In addition to this role in sleep regulation, the MCH system and the MCH receptor 1 (MCHR1) have been implicated in a wide variety of other physiological functions and behaviors, including feeding/metabolism, reward, anxiety, depression, and learning. The basic research literature on sleep and the MCH system, and the history of MCH drug development, provide cause for both skepticism and cautious optimism about the prospects of MCH-targeting drugs in sleep disorders. Extensive efforts have focused on developing MCHR1 antagonists for use in obesity, however, few of these drugs have advanced to clinical trials, and none have gained regulatory approval. Additional basic research will be needed to fully characterize the MCH system’s role in sleep regulation, for example, to fully differentiate between MCH-neuron and peptide/receptor-mediated functions. Additionally, a number of issues relating to drug design will continue to pose a practical challenge for novel pharmacotherapies targeting the MCH system.

Chronic Stress-Induced Elevation of Melanin-Concentrating Hormone in the Locus Coeruleus Inhibits Norepinephrine Production and Associated With Depression-Like Behaviors in Rats

“…MCHR1 is a G protein-coupled receptor that can couple with G i protein and inhibit cAMP-PKA signaling, resulting in lower adenylate cyclase activity, cAMP formation, and PKA levels and the inhibition of neuronal activation ( Hawes et al, 2000 ; Bencze et al, 2018 ; Potter and Burgess, 2022 ). cAMP-PKA is a major cellular signaling pathway that is involved in the regulation of depression ( Wang et al, 2018 ; Gao et al, 2022 ).…”

Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1

“…The MCH-MCHR1 system has also been implicated in regulating primary cilia growth and function [26][27][28] . MCHR1 is considered a potential therapeutic target for various diseases, including obesity, sleep disorders, anxiety disorders, schizophrenia, and Alzheimer's disease [29][30][31][32] . Numerous MCHR1 antagonists, such as SNAP-7941, AMG-076, NGD-4715, AZD1979, SNAP-94847 and RGH-076, have been developed and some have shown therapeutic effects in clinical studies 29,33 .…”

Effects of Paradoxical Sleep Deprivation on MCH and Hypocretin Systems

“…Both hypocretin and MCH receptors are distributed in approximately the same brain areas in rats, including the frontal cortex and the hippocampus. 9,10 The MCHergic and hypocretinergic neuronal groups reciprocally regulate sleep and wakefulness; [11][12][13][14] the MCH tends to promote sleep, while hypocretins are wake-promoting neuromodulators. 15 Electrophysiological studies 16 have revealed that MCHergic neurons are more active during sleep, particularly in paradoxical sleep (PS), whereas hypocretinergic neurons exhibit higher activity levels during wakefulness.…”