title: Opioid receptor probes derived from cycloaddition of the hallucinogen natural product salvinorin A.
abstract: As part of our continuing efforts toward more fully understanding the structure-activity relationships of the neoclerodane diterpene salvinorin A, we report the synthesis and biological characterization of unique cycloadducts through [4+2] Diels-Alder cycloaddition. Microwave-assisted methods were developed and successfully employed, aiding in functionalizing the chemically sensitive salvinorin A scaffold. This demonstrates the first reported results for both cycloaddition of the furan ring and functionalization via microwave-assisted methodology of the salvinorin A skeleton. The cycloadducts yielded herein introduce electron-withdrawing substituents and bulky aromatic groups into the C-12 position. Kappa opioid (KOP) receptor space was explored through aromatization of the bent oxanorbornadiene system possessed by the cycloadducts to a planar phenyl ring system. Although dimethyl- and diethylcarboxylate analogues 5 and 6 retain some affinity and selectivity for KOP receptors and are full agonists, their aromatized counterparts 13 and 14 have reduced affinity for KOP receptors. The methods developed herein signify a novel approach toward rapidly probing the structure-activity relationships of furan-containing natural products.
authors.affiliation: Division of Medicinal & Natural Products Chemistry, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Anthony
authors.initials: A
authors.lastname: Lozama
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cunningham
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Caspers
authors.forename: Justin T
authors.initials: JT
authors.lastname: Douglas
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
mesh_terms: D045785:Diterpenes, Clerodane / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005663:Furans / Q000737:chemistry; D006213:Hallucinogens / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D017473:Receptors, Opioid, kappa / Q000819:agonists*; D027544:Salvia / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D045785:Diterpenes, Clerodane; D005663:Furans; D006213:Hallucinogens; D017473:Receptors, Opioid, kappa; C090499:salvinorin A