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)

被引：9

作者：

Nagase, Hiroshi ^{[1
]}

Koyano, Koji ^{[1
]}

Wada, Naohisa ^{[1
]}

Hirayama, Shigeto ^{[1
]}

Watanabe, Akio ^{[1
]}

Nemoto, Toru ^{[1
]}

Nakajima, Mayumi ^{[2
]}

Nakao, Kaoru ^{[2
]}

Mochizuki, Hidenori ^{[2
]}

Fujii, Hideaki ^{[1
]}

机构：

[1] Kitasato Univ, Sch Pharm, Minato Ku, Tokyo 1088641, Japan

[2] Toray Industries Ltd, Pharmaceut Res Labs, Kanazawa, Ishikawa 2488555, Japan

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2011年 / 21卷 / 20期

关键词：

Cap structure; Capped homotriplet; p-Toluenesulfonylmethyl isocyanide; Opioid; Antinociception; PROTEIN-COUPLED RECEPTORS; ANTAGONIST SELECTIVITY; REARRANGEMENT; NALTREXONE; DESIGN;

D O I：

10.1016/j.bmcl.2011.07.065

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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 p receptor over the kappa receptor, and the mu selectivity was the highest among the reported p 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 mu receptor. (C) 2011 Elsevier Ltd. All rights reserved.

引用

页码：6198 / 6202

页数：5

共 24 条

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