Melatonin agonists

The development of melatonin agonists is one of the most exciting frontiers in sleep medicine.

Only discovered as a human hormone about 50 years ago, melatonin has proven to be an important part of the body’s regulation of the sleep-wake cycle.  Melatonin agonists are drugs that act like melatonin in the body – that interact with the melatonin neurons and amplify the body’s melatonin circadian signal.  They can be useful for shifting the body’s internal time clock – which helps with sleep disorders and perhaps depression.

Melatonin is a simple molecule, and not unlike many other neurotransmitters in chemical structure.  It can be classified as a monoamine, as can serotonin or histamine.  Melatonin is involved in a wide range of physiological functions including digestion.  The hormone attaches to  melatonin membrane receptors MT1 and MT2 in the central nervous system.

Melatonin has been called a "photoneuroendocrine transducer".  This somewhat strange term seems to indicate that the hormone plays are part in “transducing” circadian signals from the environment to physiological signals.

It is also widely used as a dietary supplement to correct jet lag and insomnia and possibly for other things.  Melatonin is in a lot of plants, and is extracted to form pills sold in health food stores. (In some places in Europe, melatonin is not available without a doctor’s prescription.)  One problem with these supplements is that they are not heavily regulated or vetted.  Dosages are suspect as is bioavailability – how likely the melatonin is able to get into your bloodstream – which is partly a function of the composition of the pills (fillers, etc.)

Nevertheless, melatonin has been used by millions of people – with and without doctor’s supervision – to overcome insomnia and circadian challenges like jet lag. People with disease, an aging brain, or life circumstances find themselves with blunted diurnal rhythms.

Melatonin can be used to treat such time-shifting problems as delayed sleep phase disorder, jet lag and shiftwork disorder.  Melatonin agonists can do the same.

In pharmacology "agonists" help/mimic/amplify chemicals in the body. They bind to the same receptors as the biological chemical.  Sometimes the binding is imperfect or tenuous, so the agonist activity is not perfect, but such imperfect agonists can still be useful drugs.  An "antagonist" is the opposite.  It blocks the receptors from body's signal chemical.  Antagonists stop or slow the activity of the body.

But you might think: why use a melatonin agonist if the real thing – melatonin – is cheap and available over-the-counter?  One plausible reason is reliability.  With no large company behind the melatonin on the shelves and no consistency, some doctors are reluctant to recommend patients take melatonin.

The more cynical reason relates to money.  Natural materials like melatonin cannot be patented and sellers will find it difficult to command premium prices.  Further, because melatonin is considered a dietary supplement and not a drug, it is not covered under insurance plans, so even if it were as costly as drugs, the number of people willing to pay for it out of pocket might not be particularly high. Drug companies always make sure the insurance companies will pay for their product.  It might be possible for a clever formulator to come up with a patent on a combination of melatonin with another drug or a novel way of delivering the melatonin.

If you can find a compound that isn’t melatonin, but acts like melatonin, you can patent it.  An article in the British Journal of Psychiatry concluded "there are insufficient data to decide whether the agonists are preferable to the `natural' compound."

You might wonder about melatonin antagonists.  If we can develop agonists to help people sleep, or to shift their bodies backward to the right time track, why not antagonists to keep people awake or shift them forward on the time track?  There has been interest in developing antagonists, although it seems more academic than commercial at this point – the big drug companies want to find new sleeping pills more than they want a melatonin antagonist which might have a mild stimulus action.

The Elderly

Melatonin and its agonists seem particularly helpful to older people. When people get old, both behavioral and metabolic circadian rhythms fall out of place and become disentrained from nature and social cues. This isn't some preference of crotchety seniors to defy social norms. It's biological and happened in elderly animals, too.  The suprachiasmatic nucleus master clock often loses its mojo in old age; scientists have even detected lower glucose consumption in the SCN of aged rats.

Giving older people hormones to reverse the effects of age is of dubious value when the hormones are estrogens and androgens. However, administration of supplemental melatonin does not appear to have nearly the negative side effects or risks that, say, the estrogen supplements for post-menopausal women does.  When the body loses its responsiveness to external circadian cues, melatonin or its agonists can help.

Specific Agonists

The only melatonin agonist in the pharmacy at present is ramelteon. It is marketed for insomnia and has found acceptance in the medical world, especially for mild cases of insomnia

S-20098 Agomelatine is being targeted by its developers for the antidepressant market.  It binds with MT-1 and MT-2 receptors.  It also works as an antagonist toward 5-HT2c receptors ( ) and thus effectively raises serotonin levels in the brain.  Given the close linkage between depressions and insomnia, a drug that treats both is not surprising.

Tasimelteon is also in development.  The FDA has approved it as an orphan drug for blind people with circadian disorders, and the manufacturer hopes to gain wider approval in the future.

Halogenated melatonin has been investigated and there are reports of other agonists in research labs.

These drugs can be classified as hypnotics, but not as sedatives. That's another way they differ from benzodiazepines and Z-drugs.

Other resources

Rationale for development of specific melatonin agonists

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