Opioid alternatives that relieve pain and lessen the risk of addiction are available, but they exert strong sedative effects. Another drawback is that they cannot be taken orally. Consequently, alternatives to the existing opioid alternatives are being sought.

A new search for “alternative alternatives” started with clonidine and dexmedetomidine, nonopioids that are known to engage the α2A-adrenergic receptor (ADRA2A). The search, led by researchers at the University of California, San Francisco (UCSF), focused on compounds that differed structurally from clonidine and dexmedetomidine, but still engaged ADRA2A. Some such compounds, the researchers hoped, would alleviate pain without causing sedation.

The researchers report that their search has turned up a promising set of molecules. Detailed preclinical results appeared in the journal Science, in an article titled, “Structure-based discovery of nonopioid analgesics acting through the α2A-adrenergic receptor.”

“We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential Gi and Go signaling,” the article’s authors wrote. “Several compounds … exerted on-target analgesic activity in multiple in vivo pain models without sedation.”

The authors concluded that their newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

“We showed that it’s possible to separate the analgesic and sedative effects related to this receptor, said Brian Shoichet, PhD, a professor in UCSF’s School of Pharmacy, and one of four senior authors of the study. “That makes it a very promising target for drug development.”

The research is part of a five-year grant from the Defense Advanced Research Projects Agency (DARPA), and began shortly before the COVID-19 pandemic, with the aim of finding effective pain killers that can be used together or in conjunction with opioids.

The work brings together researchers from a variety of disciplines; Shoichet’s co-authors include UCSF anatomy chair Allan Basbaum, PhD, 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, PhD, 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,” said Basbaum. “That doesn’t happen very often.”

To start the search for molecules that would bind firmly to the receptor, Shoichet computationally combed through a virtual library of over 300 million molecules, eliminating those that were too bulky for the small receptor. The remaining thousands were virtually “docked,” one by one, on a computer model of the receptor.

Through a series of tests, Shoichet narrowed the field from an initial 48 candidates to six, based on how they bound to the receptor in cultured human and mouse cells. Each of the final six was tested on three different mouse models for acute and chronic pain, and successfully alleviated pain in all three instances.

The pain-relieving molecules, which were from chemically different families, are also entirely novel. None of them had previously been synthesized.

Whereas the older drugs, like dexmedetomidine, activate a broad spectrum of neuronal pathways, the new molecules trigger only a selective subset of these, Shoichet said. The molecules also concentrate in the brain, and bind tightly to the receptor, making them good candidates for further development.

Basbaum cautions that it may take several years of research before any of the compounds could be tested in clinical trials. The researchers don’t yet understand the possible side effects of the new molecules, and whether there might be unintended consequences from long-term use.

He believes, however, that it’s unlikely the compound is addictive. “Substance abuse happens when the drug generates a reward, which we didn’t see any evidence of,” he said.

While opioids clearly help patients with pain from surgery or cancer, Basbaum noted that the majority of the 50 million Americans with chronic pain have other conditions, like back injuries, joint pain, and inflammatory disease, that often aren’t helped by the drugs. New analgesics could completely change the outlook for these patients.

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