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Drug blocks light sensors in eye that may trigger migraine attacks

Ludovic Mure, Megumi Hirota and Satchin Panda

From left: Scientists Ludovic Mure, Megumi Hirota and Satchin Panda in Salk’s Regulatory Biology Laboratory.

Scientists have known for nearly a century that humans and animals can sense light even when they can't see, and more than ten years ago, Satchidananda Panda's lab discovered that melanopsin, a receptor found in neurons connecting the eyes and brain, is responsible for sensing light independently of normal vision. Since then, researchers have determined that the receptor is vital for maintaining sleep cycles and other circadian rhythms in those with healthy vision, constricting the pupil of the eye in bright light and potentially exacerbating the light-sensitivity associated with migraines. While melanopsin senses light for these non-vision purposes, closely related receptors—rhodopsin and cone opsins—provide vision-forming information to the brain.

In a recent study published in Nature Chemical Biology, Panda reported that a new molecule that selectively blocks light-sensitive receptors in the eyes could help people with migraines or circadian rhythm imbalances without affecting normal vision.

Scientists already know of one class of compounds, retinoids, which interact with opsins, but they are non-specific and bind to melanopsin, rhodopsin and a handful of other receptors in the body, causing widespread side effects. Panda wanted something more specific, so for ten years, his group, in collaboration with scientists at the pharmaceutical company Lundbeck, has attempted to find chemical compounds that specifically shut off melanopsin in animals.

In their latest search, Panda and his collaborators turned to Lundbeck's library of compounds. A team at Lundbeck tested whether each chemical from the library turned off melanopsin; several appeared to block its function. None looked like retinoids, and the chemicals, dubbed opsinamides, also showed no interaction with rhodopsin or other opsins. To make sure they were specific to melanopsin and to determine whether they would have a physiological response in addition to binding to melanopsin, Panda's group next looked at whether the drugs affected pupillary constriction in mice. The results showed that the drugs stop melanopsin from signaling the brain when the eyes are exposed to bright light.

The compounds require further optimization in anticipation of clinical testing but are extraordinarily useful for research and as leads in the discovery process.