title: Addressing Structural Flexibility at the A-Ring on Salvinorin A: Discovery of a Potent Kappa-Opioid Agonist with Enhanced Metabolic Stability.
abstract: Previous structure-activity studies on the neoclerodane diterpenoid salvinorin A have demonstrated the importance of the acetoxy functionality on the A-ring in its activity as a κ-opioid receptor agonist. Few studies have focused on understanding the role of conformation in these interactions. Herein we describe the synthesis and evaluation of both flexible and conformationally restricted compounds derived from salvinorin A. One such compound, spirobutyrolactone 14, was synthesized in a single step from salvinorin B and had similar potency and selectivity to salvinorin A (EC50= 0.6 ± 0.2 nM at κ; >10000 nM at μ and δ). Microsomal stability studies demonstrated that 14 was more metabolically resistant than salvinorin A. Evaluation of analgesic and anti-inflammatory properties revealed similar in vivo effects between 14 and salvinorin A. To our knowledge, this study represents the first example of bioisosteric replacement of an acetate group by a spirobutyrolactone to produce a metabolically resistant derivative.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , 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 , Lawrence, Kansas 66045, United States.
authors.forename: Rachel Saylor
authors.initials: RS
authors.lastname: Crowley
authors.affiliation: School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington , Wellington 6012, New Zealand.
authors.forename: Kelly F
authors.initials: KF
authors.lastname: Paton
authors.affiliation: School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington , Wellington 6012, New Zealand.
authors.forename: Andrew
authors.initials: A
authors.lastname: Biggerstaff
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Neuenswander
authors.affiliation: Department of Chemistry, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Victor W
authors.initials: VW
authors.lastname: Day
authors.affiliation: School of Biological Sciences, Centre for Biodiscovery, Victoria University of Wellington , Wellington 6012, New Zealand.
authors.forename: Bronwyn M
authors.initials: BM
authors.lastname: Kivell
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, The University of Kansas , Lawrence, Kansas 66045, United States.
authors.forename: Thomas E
authors.identifier: 0000-0002-0649-8052
authors.initials: TE
authors.lastname: Prisinzano
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D045785:Diterpenes, Clerodane / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D008297:Male; D013058:Mass Spectrometry; D008861:Microsomes / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000819:agonists; D013056:Spectrophotometry, Ultraviolet; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D045785:Diterpenes, Clerodane; D008024:Ligands; D017473:Receptors, Opioid, kappa; C090499:salvinorin A