Discovery of conolidine derivative DS39201083 as a potent novel analgesic without mu opioid agonist activity

Tsuyoshi Arita; Masayoshi Asano; Kazufumi Kubota; Yuki Domon; Nobuo Machinaga; Kousei Shimada

doi:10.1016/j.bmcl.2019.05.045

Discovery of conolidine derivative DS39201083 as a potent novel analgesic without mu opioid agonist activity

Bioorg Med Chem Lett. 2019 Aug 1;29(15):1938-1942. doi: 10.1016/j.bmcl.2019.05.045. Epub 2019 May 21.

Authors

Tsuyoshi Arita¹, Masayoshi Asano², Kazufumi Kubota², Yuki Domon², Nobuo Machinaga², Kousei Shimada²

Affiliations

¹ R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan. Electronic address: arita.tsuyoshi.sg@daiichisankyo.co.jp.
² R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 31147104
DOI: 10.1016/j.bmcl.2019.05.045

Abstract

We discovered a novel compound, 5-methyl-1,4,5,7-tetrahydro-2,5-ethanoazocino[4,3-b]indol-6(3H)-one sulfuric acid salt (DS39201083), which was formed by derivatization of a natural product, conolidine. DS39201083 had a unique bicyclic skeleton and was a more potent analgesic than conolidine, as revealed in the acetic acid-induced writhing test and formalin test in ddY mice. The compound showed no agonist activity at the mu opioid receptor.

Keywords: Acetic acid writhing test; Analgesic; Conolidine; Indole alkaloid; Non-opioid.

MeSH terms

Analgesics, Opioid / pharmacology
Analgesics, Opioid / therapeutic use*
Animals
Indole Alkaloids / pharmacology
Indole Alkaloids / therapeutic use*
Mice
Receptors, Opioid, mu / agonists
Receptors, Opioid, mu / therapeutic use*

Substances

Analgesics, Opioid
Indole Alkaloids
Receptors, Opioid, mu
conolidine