The Discovery of Melatonin

Overview

Melatonin is not a peptide but an indoleamine derived from serotonin. It is included in peptide and hormone reference works because of its central role in neuroendocrine timing and because its discovery sits alongside the major peptide-hormone milestones of the twentieth century. Melatonin was isolated in 1958 by Aaron Lerner and colleagues at Yale University from bovine pineal tissue, during a study originally motivated by its ability to lighten amphibian skin.

The pineal gland had been known since antiquity, and Descartes famously called it "the seat of the soul," but its physiological function remained a mystery until the second half of the 20th century. Lerner's group showed that a pineal-derived substance could cause melanophore aggregation in frog skin, and by processing hundreds of thousands of bovine pineal glands, they purified enough material to determine its chemical structure: N-acetyl-5-methoxytryptamine.

Subsequent research by Julius Axelrod, Richard Wurtman, Josephine Arendt, Russel Reiter, and others established that melatonin is released in a daily rhythm, with high levels at night and low levels during the day, and that it signals darkness to downstream tissues. This made it a key molecular link between environmental light and internal biological time.

Key People

• Aaron B. Lerner (1920–2007): American dermatologist and biochemist who isolated melatonin.
• Julius Axelrod (1912–2004): Neuroscientist whose laboratory mapped the pineal biosynthetic pathway.
• Richard J. Wurtman: MIT researcher who studied pineal physiology and melatonin pharmacology.
• Josephine Arendt: British chronobiologist who pioneered clinical melatonin research.
• Russel J. Reiter: Researcher known for work on antioxidant properties of melatonin.

Timeline

• 1917: McCord and Allen note that bovine pineal extracts lighten amphibian skin.
• 1958: Lerner et al. isolate and name melatonin.
• 1960: Structure of melatonin is published.
• 1960s: Axelrod's laboratory elucidates the serotonin-to-melatonin biosynthetic pathway.
• 1970s: Daily rhythm of melatonin secretion is characterized.
• 1980s–1990s: Clinical research on shift work, jet lag, and sleep.
• 2005: Ramelteon becomes the first melatonin receptor agonist approved by the FDA for insomnia.

Background

Melatonin biosynthesis begins with tryptophan, which is converted to serotonin and then, at night, to N-acetylserotonin and finally melatonin. The enzyme arylalkylamine N-acetyltransferase (AANAT) is rate-limiting and is strongly regulated by darkness signals from the suprachiasmatic nucleus of the hypothalamus. Sympathetic innervation of the pineal gland transmits this signal to pinealocytes.

Melatonin acts via two G protein-coupled receptors, MT1 and MT2, expressed in the suprachiasmatic nucleus, retina, cardiovascular system, and other tissues. Through these receptors, melatonin phase-shifts circadian rhythms, promotes sleep at night in diurnal species, and modulates reproductive timing in seasonal animals.

Modern Relevance

Melatonin is widely used as an over-the-counter sleep aid and as a clinical tool for circadian disorders such as jet lag, shift-work sleep disorder, and delayed sleep-phase syndrome. Prescription agents include ramelteon, agomelatine, and tasimelteon, which target melatonin receptors with different selectivities. Low-dose melatonin is a well-studied chronobiotic used to shift the timing of the internal clock, while higher doses are sometimes used as a hypnotic.

Beyond sleep, melatonin is studied as a neuroprotective agent, a modulator of the immune system, and an antioxidant. The peptide research community has also explored analogs with improved half-life, receptor selectivity, or oral bioavailability. For broader neuroendocrine context, see peptides-in-neuroscience.

Related Compounds

• Melatonin
• Serotonin
• Ramelteon
• Agomelatine
• Tasimelteon