1021922-59-7Relevant articles and documents
Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability
Crowley, Rachel Saylor,Riley, Andrew P.,Sherwood, Alexander M.,Groer, Chad E.,Shivaperumal, Nirajmohan,Biscaia, Miguel,Paton, Kelly,Schneider, Sebastian,Provasi, Davide,Kivell, Bronwyn M.,Filizola, Marta,Prisinzano, Thomas E.
supporting information, p. 11027 - 11038 (2016/12/30)
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 μ-opioid receptor (MOR) agonist (EC50 = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-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.
