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10-25-22

Compounds block pain without sedation in mice

• Researchers identified several compounds that activate a specific pain-blunting receptor on cells.
• In studies in mice, the compounds blocked pain without causing the sedation seen with other drugs that target this receptor.

Drugs to better treat pain, both acute and chronic, are desperately needed. Many available drugs don't work well for some pain conditions, or in some people. Opioids, a mainstay of pain treatment, can lead to dependency, and also addiction when misused.

Drugs that target a receptor found on cells called the ?2AAR receptor can provide potent pain relief. However, these drugs also cause very strong sedation. This makes them impractical for use outside of a hospital.

An international team of researchers, funded in part by NIH, has been looking for ways to harness the painkilling effects of ?2AAR activation without causing sedation. Current drugs are thought to turn on many cell-signaling pathways controlled by ?2AAR. The unwanted side effects like sedation may result from the activation of these multiple pathways.

In a new study, the team used powerful computers to screen the structures of more than 300 million diverse molecules for their potential to interact with the a2AAR receptor. The researchers then synthesized and tested the most promising candidates in cells and mice. The results were published on Sept. 30 in Science.

The researchers focused on 48 of the top candidates that had structures unlike those of available drugs that activate ?2AAR. Of these, 30 bound to the receptor in the laboratory. Seventeen bound at levels that would make them potentially useful as a drug.

The most potent of these 17 compounds all activated ?2AAR differently than the currently available drugs. In cells, they turned on a more selective set of cell-signaling pathways.

Using cryo-electron microscopy, the researchers examined the structure of two of these compounds bound to the receptor. They then used information about their interactions to optimize the strongest of the compounds, called '9087.

The team created and tested several new compounds based on '9087 for their ability to bind to and activate ?2AAR. They tested the most potent of these, called PS75, along with '9087, in mice. Both accumulated successfully in the brain after either intravenous or oral administration.

Both compounds reduced the sensitivity of mice to pricking, heat, inflammation, and pain. When the team gave the mice another compound that blocked the activity of ?2AAR, the pain-killing effects were largely lost. This showed that the compounds worked primarily as expected, by activating ?2AAR.

The compounds didn't affect appetite or cause constipation. And importantly, neither reduced the ability of mice to navigate a rotating cylinder, showing that balance, coordination, and awareness remained intact. This confirmed that the compounds didn't have a sedative effect.

"We showed that it's possible to separate the [pain killing] and sedative effects related to this receptor," says Dr. Brian Shoichet from the University of California, San Francisco, who helped lead the study. "That makes it a very promising target for drug development."

Further testing of these compounds for multiple pain conditions, as well as for side effects, including those potentially affecting the heart, are needed before the compounds could be tested in people.

-by Sharon Reynolds

For further information on this and other health topics, visit the web site of the National Institute of Health at www.nih.gov.