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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

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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 RS   Riley Andrew P AP   Sherwood Alexander M AM   Groer Chad E CE   Shivaperumal Nirajmohan N   Biscaia Miguel M   Paton Kelly K   Schneider Sebastian S   Provasi Davide D   Kivell Bronwyn M BM   Filizola Marta M   Prisinzano Thomas E TE  

Journal of medicinal chemistry 20161213 24

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 (EC<sub>50</sub> = 1.2 nM, >8000 μ/κ selectivity). 5 is a biased activator of MOR-induced G-protein signaling over β-arrestin-2 recruitment. Metady  ...[more]

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