title: Synthesis of novel triplet drugs with 1,3,5-trioxazatriquinane skeletons and their pharmacologies. Part 2: Synthesis of novel triplet drugs with the epoxymethano structure (capped homotriplet).
abstract: An improved synthetic method for triplet drugs with the 1,3,5-trioxazatriquinane skeleton was developed that used p-toluenesulfonylmethyl isocyanide (TosMIC) instead of 1,3-dithiane. Using the improved method, we synthesized compounds with two identical pharmacophore units and an epoxymethano group, that is, capped homotriplets. Among the synthesized capped homotriplets, KNT-123 showed high selectivity for the μ receptor over the κ receptor, and the μ selectivity was the highest among the reported μ selective nonpeptide ligands. KNT-123 administered subcutaneously induced a dose-dependent analgesic effect in the acetic acid writhing assay, and its potency was 11-fold more potent than that of morphine. KNT-123 may serve as a useful tool for the study of the pharmacological actions mediated specifically via the μ receptor.
authors: School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. nagaseh@pharm.kitasato-u.ac.jp
authors: Hiroshi
authors: H
authors: Nagase
authors: Koji
authors: K
authors: Koyano
authors: Naohisa
authors: N
authors: Wada
authors: Shigeto
authors: S
authors: Hirayama
authors: Akio
authors: A
authors: Watanabe
authors: Toru
authors: T
authors: Nemoto
authors: Mayumi
authors: M
authors: Nakajima
authors: Kaoru
authors: K
authors: Nakao
authors: Hidenori
authors: H
authors: Mochizuki
authors: Hideaki
authors: H
authors: Fujii
mesh_terms: D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001952:Bridged-Ring Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008958:Models, Molecular; D009570:Nitriles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D059225:Nociception / Q000187:drug effects; D059226:Nociceptive Pain / Q000188:drug therapy*; D010147:Pain Measurement / Q000187:drug effects; D017473:Receptors, Opioid, kappa / Q000378:metabolism*; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D012717:Sesquiterpenes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use*; D014105:Tosyl Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000701:Analgesics, Opioid; D001952:Bridged-Ring Compounds; D009570:Nitriles; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu; D012717:Sesquiterpenes; D014105:Tosyl Compounds; C061881:4-toluenesulfonylmethyl isocyanide