Steering clear of opioids’ downsides

Current opioids typically cause pain relief by binding to and activating the µ-opioid receptor on nerve cell surfaces. But these opioids famously cause addiction, so scientists have been eyeing another member of the opioid receptor family, the κ-opioid receptor, as an alternative target for treating pain and intractable itch. Activating this receptor doesn’t cause the euphoric feeling that drives opioid abuse, but it’s still not a perfect target: When compounds bind to it, they can trigger an unknown biochemical pathway that leads to sedation and dysphoria, or strong feelings of unease.

Speaking at the American Chemical Society national meeting in Washington, D.C., on Sunday, Laura Bohn of Scripps Research Institute Florida described her group’s efforts to not only find κ-receptor-targeting compounds that avoid these side effects but also to uncover the signaling pathway responsible for them.

Late last year, Bohn’s team, including Jeffrey Aubé of the University of North Carolina, Chapel Hill, used cell assays to identify compounds called biased agonists that bind to the κ-opioid receptor and activate a G-protein signaling pathway but avoid a β-arrestin pathway, which the scientists think leads to sedation and dysphoria (ACS Med. Chem. Lett. 2017, DOI: 10.1021/acsmedchemlett.7b00224).

One of these biased agonists, called triazole 1.1, reduced pain and itch in mice without decreasing the animals’ locomotion or causing a drop in their dopamine levels—a sign of dysphoria.

Although the results are encouraging, accurately linking a particular pathway with corresponding physiological responses is still a major challenge for the field, said Bohn during a session in the Division of Medicinal Chemistry.

To address this issue, her team studied biased agonists for the better-known µ-opioid receptor and developed a predictive model that correlates empirical data from cell-based assays with physical outcomes in mice. The researchers screened µ-targeting compounds and observed a direct correlation between those that triggered the β-arrestin pathway in cells and those that caused respiratory depression—another common side effect of many opioids—in mice.

It’s still unknown if the β-arrestin pathway in both the µ- and κ-opioid receptor is directly causing negative side effects, Bohn said, but this correlation could be useful as a safety screen in early drug discovery.

Ultimately, this work may allow drug developers to “capitalize on the beneficial effects and get rid of the unwanted actions” in opioids, said Saint Louis University’s Daniela Salvemini, who co-organized the ACS meeting session along with Kenneth Jacobson at the National Institutes of Health.

“This type of analysis will become more important because there are probably many hidden biased agonists among experimental drugs or even approved drugs,” Jacobson said, adding that the researchers’ predictive model, which hasn’t been published yet, is “very promising.”