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.
Copyright © 2011 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Analgesics, Opioid / chemical synthesis
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Analgesics, Opioid / chemistry*
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Analgesics, Opioid / pharmacology
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Analgesics, Opioid / therapeutic use*
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Animals
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Bridged-Ring Compounds / chemical synthesis
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Bridged-Ring Compounds / chemistry*
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Bridged-Ring Compounds / pharmacology
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Bridged-Ring Compounds / therapeutic use*
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Mice
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Models, Molecular
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Nitriles / chemical synthesis
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Nitriles / chemistry
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Nitriles / pharmacology
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Nitriles / therapeutic use
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Nociception / drug effects
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Nociceptive Pain / drug therapy*
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Pain Measurement / drug effects
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Receptors, Opioid, kappa / metabolism*
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Receptors, Opioid, mu / metabolism*
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Sesquiterpenes / chemical synthesis
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Sesquiterpenes / chemistry*
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Sesquiterpenes / pharmacology
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Sesquiterpenes / therapeutic use*
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Tosyl Compounds / chemical synthesis
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Tosyl Compounds / chemistry
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Tosyl Compounds / pharmacology
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Tosyl Compounds / therapeutic use
Substances
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Analgesics, Opioid
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Bridged-Ring Compounds
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Nitriles
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Receptors, Opioid, kappa
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Receptors, Opioid, mu
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Sesquiterpenes
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Tosyl Compounds
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4-toluenesulfonylmethyl isocyanide