title: Bioisosteric modification of salvinorin A, a potent and selective kappa-opioid receptor agonist.
abstract: Salvinorin A ((2S,4aR,6aR,7R,9S,10aS, 10bR)-2H-naphtho[2,1-c]pyran-7-carboxylic acid, 9-(acetyloxy)-2-(3-furanyl)dodecahydro-6a,10b-dimethyl-4,10-dioxo methyl ester, 1, CAS 83729-01-5) has been shown to bind with high affinity and selectivity to the kappa-opioid receptor (KOR) as an agonist. Bioisosteres of 1 were developed and biologically evaluated in binding and functional assays. The C-2 thioacetate isoster produced comparable activity to 1, but nitrogen substitution had a diminishing effect. Intermediates, which lack a beta-carbonyl at C-2, displayed moderate affinity. The derivatives were tested against all opioid subtypes and were selective towards KOR.
authors.affiliation: Department of Pharmacognosy and National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, University of Mississippi, University, Mississippi 38677-1848, USA.
authors.forename: D Jeremy
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Hesham
authors.initials: H
authors.lastname: Fahmy
authors.forename: Bryan L
authors.initials: BL
authors.lastname: Roth
authors.forename: Feng
authors.initials: F
authors.lastname: Yan
authors.forename: Jordan K
authors.initials: JK
authors.lastname: Zjawiony
mesh_terms: D001667:Binding, Competitive; D002460:Cell Line; D002851:Chromatography, High Pressure Liquid; D004224:Diterpenes / Q000737:chemistry* / Q000494:pharmacology*; D045785:Diterpenes, Clerodane; D006801:Humans; D007202:Indicators and Reagents; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D011619:Psychotropic Drugs / Q000737:chemistry* / Q000494:pharmacology*; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D013055:Spectrophotometry, Infrared; D013329:Structure-Activity Relationship
chemical_list: D004224:Diterpenes; D045785:Diterpenes, Clerodane; D007202:Indicators and Reagents; D011619:Psychotropic Drugs; D017473:Receptors, Opioid, kappa; C090499:salvinorin A