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.
"The idea was that if we came up with something that was completely novel in terms of structure, it would likely have novel biology. And as luck would have it, it does," said Bryan Roth, a corresponding author on the paper, professor in the Department of Pharmacology at UNC's Eshelman School of Pharmacy and director of the NIMH Psychoactive Drug Screening Program at NIH's National Institute of Mental Health (NIMH).
Epiodyne has received seed funding from Kleiner Perkins Caufield & Byers and Mission Bay Capital, but is not disclosing the amount of funding or its immediate plans for PZM21. According to Roth, the field has converged on the notion in the last 15 years that GNAI1 signaling mediates pain relief while ARRB2 is responsible for many, if not all, of the side effects of mu receptor activation.
However, a study published two weeks ago in Nature Communications demonstrated the first positive role for ARRB2 in