Novel molecules alleviate pain, avoid sedating effect

According to new research headed by UC San Francisco scientists, a newly found group of molecules relieved pain in mice whilst preventing the sedating effect that limits the usage of opiates. The molecules interact with the same receptor as clonidine and dexmedetomidine, two sedatives routinely used in hospitals, but they are chemically unrelated and may not be addictive.

Clonidine and dexmedetomidine are also powerful pain relievers, but they are so sedating that they are seldom used outside of the hospital.

We showed that it’s possible to separate the analgesic and sedative effects related to this receptor. That makes it a very promising target for drug development.”

Brian Shoichet PhD, Study Senior Author and Professor, School of Pharmacy, University of California–San Francisco

The research was published on September 30^th, 2022, in the journal Science.

The study is part of a five-year program from the Defense Advanced Research Projects Agency (DARPA) and commenced shortly before the COVID-19 outbreak, with the goal of discovering potent painkillers that may be used alongside or in addition to opioids.

The study team includes UCSF anatomy chair Allan Basbaum, Ph.D., chemist Peter Gmeiner of Freidrichs Alexander University in Germany, structural biologist Yang Du, PhD, of the Chinese University of Hong Kong, and molecular biologist Michel Bouvier, Ph.D., of the University of Montreal.

Together, we were able to take this from the most fundamental level to identifying new molecules that might be relevant, and then to demonstrating that, in fact, they are relevant. That doesn’t happen very often.”

Allan Basbaum, Anatomy Chair, University of California–San Francisco

Six molecules out of 300 million

Basbaum, who had examined this adrenergic receptor named alpha2a in his lab and discovered that it is linked to pain alleviation, urged Shoichet to investigate molecules that would activate it.

Shoichet computationally scanned through a virtual library of over 300 million molecules to begin the hunt for compounds that would firmly attach to the receptor, removing those that were too heavy for the small receptor. The remaining thousands were virtually “docked” on a computer model of the receptor one by one.

Shoichet refined the field from 48 choices to six through a series of experiments depending on how they bind to the receptor in cultured human and mouse cells. Each of the remaining six was evaluated on three distinct mice models of acute and chronic pain, and all three successfully eased the pain.

The pain-relieving compounds, which come from distinct chemical families, are also completely new. None of them had ever been synthesized before.

Whereas previous medications, such as dexmedetomidine, engage a wide range of neural pathways, the new compounds only activate a subset of these, according to Shoichet. The compounds also congregate in the brain and bind strongly to the receptor, making them promising candidates for further research.

Hope for one in five Americans

Basbaum warns that it could take years of investigation before any of the molecules are tested in clinical trials. The investigators are still exploring the new molecules’ potential side effects and whether there will be any unforeseen consequences from long-term use.

He believes, however, that the molecule is unlikely to be addictive.

Substance abuse happens when the drug generates a reward, which we didn’t see any evidence of.”

Allan Basbaum, Anatomy Chair, University of California–San Francisco

While opioids certainly benefit patients suffering from post-surgical or cancer pain, Basbaum added that the bulk of the 50 million Americans suffering from chronic pain has other diseases, such as back injuries, joint pain, and inflammatory disease, that are frequently unaffected by the drugs. New analgesics could drastically change these patients’ lives.

Basbaum concludes, “If we can create a drug that works in combination with a much lower dose of opiate, that would be the dream. The need for that is huge.”