title: Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 1: Synthesis of triplet drugs with morphinan skeletons.
abstract: We synthesized symmetrical and nonsymmetrical triplet drugs with 1,3,5-trioxazatriquinane skeletons. The isolation of key intermediates, oxazoline dimers, made it possible to effectively produce nonsymmetrical triplets. Among the synthesized triplets, KNT-93, composed of three identical opioid μ receptor agonists, showed dose-dependent antinociception via the μ receptor. The effect was 56-fold more potent than that of morphine, a representative μ agonist. The profound analgesic effect induced by KNT-93 might result from simultaneous occupation of three μ opioid receptors.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. nagaseh@pharm.kitasato-u.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
authors.forename: Akio
authors.initials: A
authors.lastname: Watanabe
authors.forename: Toru
authors.initials: T
authors.lastname: Nemoto
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nakajima
authors.forename: Ko
authors.initials: K
authors.lastname: Hasebe
authors.forename: Hidenori
authors.initials: H
authors.lastname: Mochizuki
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
mesh_terms: D000700:Analgesics / Q000138:chemical synthesis* / Q000737:chemistry; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D015394:Molecular Structure; D009019:Morphinans / Q000737:chemistry*; D009271:Naltrexone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D017450:Receptors, Opioid, mu / Q000819:agonists
chemical_list: D000700:Analgesics; D001952:Bridged-Ring Compounds; C562364:KNT 93; D009019:Morphinans; D017450:Receptors, Opioid, mu; D009271:Naltrexone