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)

Hiroshi Nagase; Koji Koyano; Naohisa Wada; Shigeto Hirayama; Akio Watanabe; Toru Nemoto; Mayumi Nakajima; Kaoru Nakao; Hidenori Mochizuki; Hideaki Fujii

doi:10.1016/j.bmcl.2011.07.065

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)

Bioorg Med Chem Lett. 2011 Oct 15;21(20):6198-202. doi: 10.1016/j.bmcl.2011.07.065. Epub 2011 Jul 26.

Authors

Hiroshi Nagase¹, Koji Koyano, Naohisa Wada, Shigeto Hirayama, Akio Watanabe, Toru Nemoto, Mayumi Nakajima, Kaoru Nakao, Hidenori Mochizuki, Hideaki Fujii

Affiliation

¹ School of Pharmacy, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan. nagaseh@pharm.kitasato-u.ac.jp

PMID: 21889335
DOI: 10.1016/j.bmcl.2011.07.065

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Analgesics, Opioid / chemical synthesis
Analgesics, Opioid / chemistry*
Analgesics, Opioid / pharmacology
Analgesics, Opioid / therapeutic use*
Animals
Bridged-Ring Compounds / chemical synthesis
Bridged-Ring Compounds / chemistry*
Bridged-Ring Compounds / pharmacology
Bridged-Ring Compounds / therapeutic use*
Mice
Models, Molecular
Nitriles / chemical synthesis
Nitriles / chemistry
Nitriles / pharmacology
Nitriles / therapeutic use
Nociception / drug effects
Nociceptive Pain / drug therapy*
Pain Measurement / drug effects
Receptors, Opioid, kappa / metabolism*
Receptors, Opioid, mu / metabolism*
Sesquiterpenes / chemical synthesis
Sesquiterpenes / chemistry*
Sesquiterpenes / pharmacology
Sesquiterpenes / therapeutic use*
Tosyl Compounds / chemical synthesis
Tosyl Compounds / chemistry
Tosyl Compounds / pharmacology
Tosyl Compounds / therapeutic use

Substances

Analgesics, Opioid
Bridged-Ring Compounds
Nitriles
Receptors, Opioid, kappa
Receptors, Opioid, mu
Sesquiterpenes
Tosyl Compounds
4-toluenesulfonylmethyl isocyanide