Melatonin receptors as therapeutic targets in the suprachiasmatic nucleus

ABSTRACT

Introduction: Disorders of rhythmicity can cause a variety of pathologies and are known to impair processes involved in metabolism, as well as in cardiovascular disease and cancer. Developing strategies to treat or prevent such diseases is a new challenge for medicine. Rhythms depend on a complex multi-oscillatory circadian network which, in mammals, is hierarchically organized with the suprachiasmatic nuclei (SCN) as master clock. The SCN, thus form an ideal structure for target discovery in circadian pathologies.

Areas covered: The development of strategies to treat or prevent disorders of rhythmicity is a new challenge for medicine. Several pharmacological approaches have been suggested, but until now, it has been mostly melatonin (MTL) or MTL-agonists which have demonstrated usefulness in modulating clock activities in vivo. A great number of structurally different MTL receptor ligands have been developed, some of which are already approved and marketed as drugs. The MTL receptor involved in phase-shifting circadian rhythms (chronobiotic effect) is the MT₁ subtype.

Expert opinion: As the two receptor subtypes for MTL may have divergent functions, the development of highly selective MT₁ and MT₂ agonists (and antagonists) is key for the discovery of novel therapeutic agents in specifically defined circadian pathologies. The identification of cells expressing the different MTL receptor subtypes should also permit a better understanding of MLT physiology/pharmacology.

KEYWORDS:

• Circadian clock
• circadian derived diseases
• melatonin
• melatonin receptors
• suprachiasmatic nuclei

Article highlights

• Disorders of rhythmicity can cause a variety of pathologies (e.g. neurological, psychiatric or sleep disorders) and are known to impair processes, resulting in metabolic disorders (obesity, diabetes, hypercholesterolemia), as well as cardiovascular disease and cancer.

• To develop counteractive strategies to treat such diseases is a new challenge for science and medicine.

• The circadian rhythms depend on a complex multioscillatory network, in mammals, in the form of a hierarchical network, with a master clock located in the suprachiasmatic nuclei (SCN) and peripheral oscillators throughout the body.

• The SCN, being the master clock, becomes the ideal structure for target discovery and chemical biology in circadian-dependent pathologies.

• Within the family of ‘modifiers’, chronobiotic drugs able to influence the phase/period of the circadian clock have to be considered. In vivo, the best-known and the most studied chronobiotic drug is melatonin (MTL).

• MTL exerts its effects principally throughout high-affinity receptors. Different subtypes have been cloned and characterized. It appears that the chronobiotic effect of MLT depends exclusively on the SCN MT₁ subtype.

• A great number of structurally different nonspecific melatonin receptor ligands have been developed (some of them already being proposed as drugs). As the two receptors for MTL may have divergent functions, the need to synthesize specific ligands is crucial for further pharmacological development and will be at the root of innovative therapeutic agents for identified pathologies.

• The phenotyping of cells (including neurons) expressing the different MTL receptor subtypes is a high priority to develop new drugs.

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Acknowledgments

The author is grateful to Dr E. Challet, Dr M. Masson-Pévet, Dr P. Klosen, Dr MP Felder-Schmittbuhl, Dr B Guardiola and C. Schuster-Klein for discussions and suggestions and to Dr D. Hicks for editorial corrections.

Declaration of interest

This work has been supported by Le Centre national de la recherche scientifique (CNRS), the University of Strasbourg, and Servier – France. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.