A research team comprised of scientists from UC San Francisco, Stanford University, the University of North Carolina (UNC), and the Friedrich-Alexander University Erlangen-Nürnberg in Germany, has announced the discovery of a novel opioid that blocks pain as effectively as morphine but is free of the adverse effects of other opioid drugs. If the findings derived from mouse models are borne out, the authors assert, the discovery could revolutionize both pain management and the battle to control the epidemic of prescription painkiller abuse, misuse, and death. The new molecule, labeled PZM21 by the study team, appears to affect opioid circuits in the brain only, without targeting other opioid receptors in the spinal cord. Additionally, tests on mice demonstrated that PZM 21 did not induce respiratory depression, nor did the treated mice exhibit the typical signs of hyperactivity and reward-seeking that would be consistent with addictive behavior. Co-senior author Brian Shoichet, PhD, professor of pharmaceutical chemistry at UCSF School of Pharmacy, commented, “Morphine transformed medicine, but it’s obviously dangerous too. People have been searching for a safer replacement for standard opioids for decades.”
Key to the discovery of the new molecule was an entirely fresh approach to drug development, in which the team started with the recently deciphered atomic structure of the mu-opioid receptor. Applying a computational approach called molecular docking, some 4 trillion—that’s 4,000,000,000,000—virtual chemical alternatives were then tested against this structure to identify specific combinations that activated the receptor without stimulating beta-arrestin2, part of the pathway linked to respiratory suppression and constipation. 23 candidate molecules suggested by the computer simulation were tested in mouse models to identify PZM21, which is chemically unrelated of existing opioid drugs. Of the developmental approach, co-senior author Brian Kobilka, MD, professor of molecular and cellular physiology at the Stanford University School of Medicine, said, “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.” The findings were published online last week in the journal Nature.
A news story about the discovery may be read here.
The journal abstract may be read here.
Posted on August 19, 2016