Biased against pain

In a departure from the rote tweaking of morphinan structures to find better and safer opioids, an academic collaboration has used a powerful, computer-based screen of more than 3 million molecules to identify a new structure that acts as a biased agonist at mu receptors, teasing apart analgesia from abuse liability and respiratory depression. The team, headed by researchers at four universities, is spinning out Epiodyne Inc. to bring the compound to the clinic.

In the study, published Aug. 17 in Nature, researchers from the University of California San Francisco (UCSF), University of North Carolina at Chapel Hill, Stanford University and the University of Erlangen-Nuremberg identified PZM21, a molecule they describe as both a research probe and a therapeutic lead, and demonstrated it has orders of magnitude greater potency at signaling via the receptor's G protein, GNAI1, than its β-arrestin, ARRB2...