‘Weird and Cool’ Discovery Could Lead to Safer Opioid

By Pat Anson, Editor

A “weird and cool” discovery by a team of international researchers could lead to the development of a new opioid medication that relieves pain without the risk of abuse and overdose.

In a case of reverse engineering, scientists in the U.S. and Germany deciphered the atomic structure of the brain’s mu-opioid receptor and then designed a drug – called PZM21 – that activates the receptor without the typical side effects of opioids. In experiments on mice, PZM21 did not cause drug-seeking behavior and did not interfere with breathing – the main cause of death in opioid overdoses.

“With traditional forms of drug discovery, you’re locked into a little chemical box,” said Brian Shoichet, PhD, a professor of pharmaceutical chemistry at UC San Francisco’s School of Pharmacy.

“But when you start with the structure of the receptor you want to target, you can throw all those constraints away. You’re empowered to imagine all sorts of things that you couldn’t even think about before.”

Shoichet and colleagues at Stanford University, the University of North Carolina and the Friedrich Alexander University in Erlangen, Germany published their findings in the journal Nature.

"This promising drug candidate was identified through an intensively cross-disciplinary, cross-continental combination of computer-based drug screening, medicinal chemistry, intuition and extensive preclinical testing," said Brian Kobilka, MD, a Nobel Prize winner and professor of molecular and cellular physiology at Stanford. It was Kobilka who first established the molecular structure of the opioid receptor.

Shoichet and his research team conducted roughly four trillion “virtual experiments” on UCSF computers, simulating how millions of different drug candidates could turn and twist in millions of different angles – called “molecular docking” -- to see how they fit into a pocket on the receptor and activate it. They avoided using molecules linked to the respiratory suppression and constipation typical of other opioids.

This led to the development of PZM21, which efficiently blocked pain in mice without producing the constipation and breathing suppression typical of other opioids. PZM21 also appears to dull pain by affecting opioid circuits in the brain only, with little effect on opioid receptors in the spinal cord. No other opioid has that effect, which Shoichet says is “unprecedented, weird and cool.”

The drug also didn’t produce the hyperactivity that other opioids trigger in mice by activating the brain’s dopamine systems. The mice did not display drug-seeking behavior by spending more time in chambers where they had previously received doses of PZM21.

“After we replicated the lab experiments and mouse studies several times, then I became excited about the potential of this new drug,” said Bryan Roth, MD, a professor of pharmacology and medicinal chemistry at University of North Carolina.

Researchers say more work is needed to establish that PZM21 is truly non-addictive, and to confirm that it is safe and effective in humans.

 “We haven’t shown this is truly non-addictive,” Shoichet cautioned. “At this point we’ve just shown that mice don’t appear motivated to seek out the drug.”