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

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.