title: Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. 3: synthesis of novel triplet drugs with the bis(epoxymethano) or bis(dimethylepoxymethano) structure (double-capped triplet).
abstract: Novel double-capped triplet drugs, which have one pharmacophore unit and two epoxymethano or dimethylepoxymethano structures (termed cap or diMe-cap structures, respectively) were synthesized. Key intermediate oxazoline 16 derived from acetone enabled the effective synthesis of double-capped triplets. SYK-134 (7a) and SYK-135 (8a) with N-cyclopropylmethyl substituent and cap structures showed selectivities for the κ opioid receptor. On the other hand, the N-Me series exhibited selectivities for the μ opioid receptor. The double-capped triplet drugs with diMe-cap structures preferred the μ receptor independently of their N-substituents. SYK-385 (19b), one of the μ-selective double-capped triplet drugs, showed the highest selectivity for the μ receptor among the reported μ-selective nonpeptide ligands.
authors.affiliation: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
authors.forename: Naohisa
authors.initials: N
authors.lastname: Wada
authors.forename: Hideaki
authors.initials: H
authors.lastname: Fujii
authors.forename: Koji
authors.initials: K
authors.lastname: Koyano
authors.forename: Shigeto
authors.initials: S
authors.lastname: Hirayama
authors.forename: Takashi
authors.initials: T
authors.lastname: Iwai
authors.forename: Toru
authors.initials: T
authors.lastname: Nemoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nagase
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008697:Methane / Q000031:analogs & derivatives / Q000737:chemistry*; D051379:Mice; D015394:Molecular Structure; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C581077:1,3,5-trioxazatriquinane; D006576:Heterocyclic Compounds, 4 or More Rings; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D008697:Methane