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Review
. 2025 Sep;45(5):1515-1539.
doi: 10.1002/med.22117. Epub 2025 May 8.

The Therapeutic Potential of Melatonin and Its Novel Synthetic Analogs in Circadian Rhythm Sleep Disorders, Inflammation-Associated Pathologies, and Neurodegenerative Diseases

Rodrigo F N Ribeiro  1   2   3 , Marco Rios Santos  3 , Maria Aquino  3 , Luis Pereira de Almeida  1   2   3 , Cláudia Cavadas  1   2   3 , Maria Manuel C Silva  1   2   3
Affiliations
Review

The Therapeutic Potential of Melatonin and Its Novel Synthetic Analogs in Circadian Rhythm Sleep Disorders, Inflammation-Associated Pathologies, and Neurodegenerative Diseases

Rodrigo F N Ribeiro et al. Med Res Rev. 2025 Sep.

Abstract

Melatonin, N-acetyl-5-methoxytryptamine, is a tryptophan-derived hormone mostly produced in the pineal gland, despite being synthesized locally at several tissues and organs. This production is rhythmically controlled by complex clock gene networks in the master pacemaker located in the suprachiasmatic nucleus of the hypothalamus. Melatonin is usually secreted only during the dark phase of the day and is essential to synchronize circadian rhythms and neuroendocrine physiological processes. Its main clinical use is associated with the treatment of jet lag and other circadian rhythm sleep disorders, with a growing number of other promising therapeutic applications due to the diverse physiological roles of melatonin. In this review, we explore melatonin and its receptors and provide an updated overview on research concerning the role of melatonin, either as an endogenous molecule or as a drug, in: sleep-wake cycle regulation; circadian rhythms; inflammatory processes that may compromise cardiovascular, respiratory, gastrointestinal, renal, and reproductive system functions; and neurodegenerative disorders such as Alzheimer's and Parkinson's disease. The most recent and promising research findings concerning melatonin synthetic analogs such as agomelatine and ramelteon are highlighted, pointing toward new compounds with promising pharmacological activity while emphasizing their structural differences and advantages when compared to melatonin.

Keywords: circadian rhythms; inflammation; medicinal chemistry; melatonin; neurodegeneration.

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