Designing more effective opioids

NIH | SEPTEMBER 17, 2016

Opioids are a class of powerful pain-relieving drugs that work by activating opioid receptors on nerve cells in the body and brain. These pain relievers are generally safe when taken for a short time and as prescribed by a doctor, but are frequently misused because they also produce euphoria. When misused or abused, opioid pain relievers can be addictive and dangerous.

A computer model of the synthesized pain relieving compound PZM21 (blue) docked with the mu opioid receptor (grey). Image credit: Dr. Bryan Roth, University of North Carolina

Scientists have identified 3 types of opioid receptors: mu, delta, and kappa. The mu receptors are responsible for opioids’ pleasurable effects and ability to relieve pain. Studies suggest that once activated, the mu receptor turns on 2 signaling pathways.

One pathway, mediated by the G protein Gi, underlies opioids’ pain-relieving properties. The other, mediated by the beta-arrestin protein, leads to the undesirable side effects of opioids, such as constipation and slowed breathing.

To search for a potential pain reliever with fewer side effects than current opioids, a research team from the University of North Carolina and the University of California, San Francisco, screened more than 3 million compounds for those that may be able to turn on the Gi-mediated pathway, but not beta-arrestin.

Using computer modeling, the scientists evaluated each compound in over 1 million structural configurations to determine how well the molecules can physically interact with the mu receptor.

The team chose 23 molecules for further pharmacological testing. The researchers then focused on optimizing the structure of the most potent molecule, which strongly activated the Gi pathway but had little effect on beta-arrestin. The resulting compound, called PZM21, was assessed for its effects on pain in mice.

Mice treated with PZM21 showed pain relief comparable to those treated with the opioid morphine, but the effects lasted longer. Unlike morphine, PZM21 did not slow the animals’ breathing, and it caused less constipation.

Further, PZM21-treated mice didn’t display the drug-seeking behaviors of those given morphine, suggesting that the drug may have less addictive potential.

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