New insight into melatonin could lead to better sleep drugs

Melatonin is a neurohormone that regulates our biological clock, and melatonin supplements are widely used to relieve sleeping disorders. But scientists don’t fully understand how the hormone interacts with two cellular receptors to do the job. Now an international team of researchers has shed some light on the receptors’ structures, which they believe could help improve the design of drugs to treat sleep disorders.

The team, led by the University of Southern California, characterized the structures of the melatonin receptors MT1 and MT2 using X-rays. The receptors were combined with four agonists that activate them: insomnia drug Rozerem (ramelteon), two melatonin analogues, and a melatonin-serotonin combo antidepressant called Valdoxan (agomelatine).

"Our goal is to provide the structural information to other researchers who can use it for designing new drug compounds or study mutations of these receptors in patients," team leader Vadim Cherezov of USC, said in an article posted by USC. 

Melatonin maintains the sleep-wake cycle by working through its receptors. MT1 in particular plays a key role in circadian rhythm. However, drugs that selectively target MT1 remain elusive. So understanding the structural differences between the two receptors could lay the molecular foundation for the design of drugs with higher specificity, the researchers argued.

The scientists found that both receptors have narrow channels buried in the fatty membranes of cells that only allow melatonin—which is both water- and oil-friendly—to pass through while blocking serotonin, which only likes water. MT2, however, also has a narrow opening in the extracellular part of the receptor.

"By comparing the 3D structures of the MT1 and MT2 receptors, we can better discern the unique, structural differences that distinguish the two receptors from each other—and their roles in the biological clock," the studies’ co-author Wei Liu of Arizona State University said in the USC article. "Armed with this knowledge, it becomes easier to design drug-like molecules that will bind to only one receptor or the other, but not both. This selective binding is important as it will minimize unwanted side-effects."

Melatonin maintains the sleep-wake cycle by working through its receptors. MT1 in particular plays a key role in circadian rhythm. However, drugs that selectively target MT1 remain elusive. So understanding the structural differences between the two receptors could lay the molecular foundation for the design of drugs with higher specificity, the researchers argued.

The scientists found that both receptors have narrow channels buried in the fatty membranes of cells that only allow melatonin—which is both water- and oil-friendly—to pass through while blocking serotonin, which only likes water. MT2, however, also has a narrow opening in the extracellular part of the receptor.

"By comparing the 3D structures of the MT1 and MT2 receptors, we can better discern the unique, structural differences that distinguish the two receptors from each other—and their roles in the biological clock," the studies’ co-author Wei Liu of Arizona State University said in the USC article. "Armed with this knowledge, it becomes easier to design drug-like molecules that will bind to only one receptor or the other, but not both. This selective binding is important as it will minimize unwanted side-effects."

MT1 and MT2 belong to a large family of receptors known as G protein-coupled receptors (GPCRs) that are of much interest to the biopharma industry because of their roles in different diseases. In fact, about a third of all marketed drugs act by binding to GPCRs, according to Nature. Boehringer Ingelheim recently signed a deal with Domain Therapeutics’ GPCR capabilities to develop new drugs for central nervous system disorders, after Merck KGaA inked a pact to apply Domain’s platform to cancer therapies. Escient Pharmaceuticals, a startup launched last May with $40 million in series A, is also going after GPCRs for a variety of indications.

"The elucidation of the crystal structures for the MT1 and MT2 receptors opens up an exciting new chapter for the development of drugs to treat sleep or circadian rhythm disorders known to cause psychiatric, metabolic, oncological and many other conditions," Margarita L. Dubocovich, who pioneered the identification of functional melatonin receptors in the early 80s, said in a statement.

The USC-led team also identified several mutations on the MT2 receptor that are associated with Type 2 diabetes, seeing for the first time the exact location of those alterations.

Next, the researchers plan to examine how the MT1 and MT2 receptors respond to antagonists, and they hope to study how other GPCRs operate the body.

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