Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting ? Opioid Analgesic with Reduced Abuse Liability.

ABSTRACT: Opioids are widely used to treat millions suffering from pain, but their analgesic utility is limited due to associated side effects. Herein we report the development and evaluation of a chemical probe exhibiting analgesia and reduced opioid-induced side effects. This compound, kurkinorin (5), is a potent and selective ?-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 ?/? selectivity). 5 is a biased activator of MOR-induced G-protein signaling over ?-arrestin-2 recruitment. Metadynamics simulations of 5's binding to a MOR crystal structure suggest energetically preferred binding modes that differ from crystallographic ligands. In vivo studies with 5 demonstrate centrally mediated antinociception, significantly reduced rewarding effects, tolerance, and sedation. We propose that this novel MOR agonist may represent a valuable tool in distinguishing the pathways involved in MOR-induced analgesia from its side effects.

SUBMITTER: Crowley RS 

PROVIDER: S-EPMC5189922 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature