The Plasma Membrane may Serve as a Drug Depot to Drive the Extreme Potency of Fentanyl.

ABSTRACT: The drug overdose crisis in the United States is driven largely by the ultrapotent synthetic (UPS) opioid fentanyl; however, fentanyl's extreme potency is poorly understood. Here we used state-of-the-art molecular dynamics simulations and experiments to test a hypothesis that fentanyl's extreme potency is driven by its ability to partition into the plasma membrane, creating a drug reservoir near the receptor. The estimated effective permeability of fentanyl at pH 7.5 is on the order of 10^-7 cm/s - at least two orders of magnitude faster than morphine. In contrast, isotonitazene (a newly emerged UPS opioid) and naloxone (an antagonist) effectively do not partition into the membrane under the same conditions. The simulations captured the proton-coupled permeation processes, challe

SUBMITTER: Clayton J 

PROVIDER: S-EPMC12330492 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature