title: Synthetic Studies of Neoclerodane Diterpenes from Salvia divinorum: Identification of a Potent and Centrally Acting μ 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 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.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott, Lawrence, Kansas 66045, United States.
authors.forename: Rachel Saylor
authors.initials: RS
authors.lastname: Crowley
authors.affiliation: Department of Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Riley
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott, Lawrence, Kansas 66045, United States.
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Sherwood
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott, Lawrence, Kansas 66045, United States.
authors.forename: Chad E
authors.initials: CE
authors.lastname: Groer
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington , Wellington 6140, New Zealand.
authors.forename: Nirajmohan
authors.initials: N
authors.lastname: Shivaperumal
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington , Wellington 6140, New Zealand.
authors.forename: Miguel
authors.initials: M
authors.lastname: Biscaia
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington , Wellington 6140, New Zealand.
authors.forename: Kelly
authors.initials: K
authors.lastname: Paton
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Schneider
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors.forename: Davide
authors.initials: D
authors.lastname: Provasi
authors.affiliation: Centre for Biodiscovery, School of Biological Sciences, Victoria University of Wellington , Wellington 6140, New Zealand.
authors.forename: Bronwyn M
authors.initials: BM
authors.lastname: Kivell
authors.affiliation: Department of Pharmacological Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, United States.
authors.forename: Marta
authors.identifier: 0000-0002-4382-8276
authors.initials: M
authors.lastname: Filizola
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , 1251 Wescoe Hall Drive, 4070 Malott, Lawrence, Kansas 66045, United States.
authors.forename: Thomas E
authors.identifier: 0000-0002-0649-8052
authors.initials: TE
authors.lastname: Prisinzano
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D004224:Diterpenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D004305:Dose-Response Relationship, Drug; D008297:Male; D015394:Molecular Structure; D010146:Pain / Q000188:drug therapy*; D010147:Pain Measurement; D051381:Rats; D017207:Rats, Sprague-Dawley; D017450:Receptors, Opioid, mu / Q000819:agonists*; D027544:Salvia / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D004224:Diterpenes; D045785:Diterpenes, Clerodane; D017450:Receptors, Opioid, mu; C468586:neoclerodane