title: Transformation of naltrexone into mesembrane and investigation of the binding properties of its intermediate derivatives to opioid receptors.
abstract: We transformed naltrexone (5) with the morphinan skeleton into mesembrane (4) belonging to the Sceletium alkaloids via key intermediate 6, characterized by a cis-fused hydroindole skeleton with a suspended phenyl ring fixed by an epoxy bridge. We then investigated the binding affinities of 4 and the key intermediate 6 derivatives to the opioid receptors. Among the tested compounds, 15', with a cis-fused hydroindole core, bound to the three opioid receptor types with strong to moderate affinities. The observed differences of binding affinities among the tested compounds were reasonably explained by the conformational analyses of the compounds. The structure-activity relationship (SAR) of the tested compounds like 15' with the hydroindole structure was completely different from the reported SAR of morphinan derivatives with the hydroisoquinoline skeleton. Compound 15' with a structure that differs from the morphinans represents a useful fundamental skeleton with a novel chemotype that may contribute to the development of new opioid ligands.
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Kazuya
authors.initials: K
authors.lastname: Konoura
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: fujiih@pharm.kitasato-u.ac.jp.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Imaide
authors.affiliation: School of Pharmacy, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Gouda
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hirayama
authors.affiliation: Department of Physical Chemistry for Drug Design, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Hirono
authors.affiliation: Department of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan; International Institute for Integrative Sleep Medicine (WPI-IIIS), University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8577, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D015195:Drug Design; D006801:Humans; D026121:Indole Alkaloids / Q000737:chemistry* / Q000378:metabolism; D008024:Ligands; D008566:Membranes / Q000378:metabolism; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism; D011957:Receptors, Opioid / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C583555:3a-(3,4-dimethoxyphenyl)-1-methyloctahydro-1H-indol-6-ol; D026121:Indole Alkaloids; D008024:Ligands; D011957:Receptors, Opioid; C000601702:mesembrenone; D009271:Naltrexone
keywords: Conformational analysis; Mesembrane; Opioid; Sceletium alkaloids