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J Med Chem. 2016 Dec 22;59(24):11027-11038. doi: 10.1021/acs.jmedchem.6b01235. Epub 2016 Dec 13.

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

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Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott, Lawrence, Kansas 66045, United States.
Department of Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington , Wellington 6140, New Zealand.
Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.


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.

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