Structure-based design of bitopic ligands for the µ-opioid receptor.

ABSTRACT: Mu-opioid receptor (µOR) agonists such as fentanyl have long been used for pain management, but are considered a major public health concern owing to their adverse side effects, including lethal overdose¹. Here, in an effort to design safer therapeutic agents, we report an approach targeting a conserved sodium ion-binding site² found in µOR³ and many other class A G-protein-coupled receptors with bitopic fentanyl derivatives that are functionalized via a linker with a positively charged guanidino group. Cryo-electron microscopy structures of the most potent bitopic ligands in complex with µOR highlight the key interactions between the guanidine of the ligands and the key Asp^2.50 residue in the Na⁺ site. Two bitopics (C5 and C6 guano) m

SUBMITTER: Faouzi A 

PROVIDER: S-EPMC10328120 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature