Fentanyl-Type Antagonist of the μ-Opioid Receptor: Important Role of Axial Chirality in the Active Conformation.

ABSTRACT: In recent years, synthetic opioids have emerged as a predominant cause of drug-overdose-related fatalities, causing the "opioid crisis." To design safer therapeutic agents, we accidentally discovered μ-opioid receptor (MOR) antagonists based on fentanyl with a relatively uncomplicated chemical composition that potentiates structural modifications. Here, we showed the development of novel atropisomeric fentanyl analogues that exhibit more potent antagonistic activity against MOR than naloxone, a morphinan MOR antagonist. Derivatives displaying stable axial chirality were synthesized based on the amide structure of fentanyl. The aS- and aR-enantiomers exerted antagonistic and agonistic effects on the MOR, respectively, and each atropisomer interacted with the MOR by assuming a

SUBMITTER: Arita H 

PROVIDER: S-EPMC11215721 | biostudies-literature | 2024 Jun

REPOSITORIES: biostudies-literature