TY - JOUR
T1 - Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum
T2 - Identification of a Potent and Centrally Acting μ Opioid Analgesic with Reduced Abuse Liability
AU - Crowley, Rachel Saylor
AU - Riley, Andrew P.
AU - Sherwood, Alexander M.
AU - Groer, Chad E.
AU - Shivaperumal, Nirajmohan
AU - Biscaia, Miguel
AU - Paton, Kelly
AU - Schneider, Sebastian
AU - Provasi, Davide
AU - Kivell, Bronwyn M.
AU - Filizola, Marta
AU - Prisinzano, Thomas E.
N1 - Publisher Copyright:
© 2016 American Chemical Society.
PY - 2016/12/22
Y1 - 2016/12/22
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85007155132&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85007155132&partnerID=8YFLogxK
U2 - 10.1021/acs.jmedchem.6b01235
DO - 10.1021/acs.jmedchem.6b01235
M3 - Article
C2 - 27958743
AN - SCOPUS:85007155132
SN - 0022-2623
VL - 59
SP - 11027
EP - 11038
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 24
ER -