Discovery of a novel bicyclic compound, DS54360155, as an orally potent analgesic without mu-opioid receptor agonist activity

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

doi:10.1016/j.bmcl.2019.126748

Discovery of a novel bicyclic compound, DS54360155, as an orally potent analgesic without mu-opioid receptor agonist activity

Bioorg Med Chem Lett. 2019 Dec 1;29(23):126748. doi: 10.1016/j.bmcl.2019.126748. Epub 2019 Oct 19.

Authors

Tsuyoshi Arita¹, Masayoshi Asano², Kazufumi Kubota³, Yuki Domon³, Nobuo Machinaga², Kousei Shimada²

Affiliations

¹ Medicinal Chemistry Research Laboratories, 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 Medicinal Chemistry Research Laboratories, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
³ Specialty Medicine Research Laboratories I, R&D Division, Daiichi Sankyo Co., Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.

PMID: 31676224
DOI: 10.1016/j.bmcl.2019.126748

Abstract

We synthesized derivatives of a natural alkaloid, conolidine, and evaluated these derivatives in the acetic acid-induced writhing test and formalin test in ddY mice after oral administration. As a result, we identified (5S)-6-methyl-1,3,4,5,6,8-hexahydro-7H-2,5-methano[1,5]diazonino[7,8-b]indol-7-one sulfate salt, 15a (DS54360155), with a unique and original bicyclic skeleton, as an analgesic more potent than conolidine. Moreover, 15a did not exhibit mu-opioid receptor agonist activity.

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

MeSH terms

Analgesics / pharmacology
Analgesics / therapeutic use*
Animals
Disease Models, Animal
Humans
Mice
Receptors, Opioid, mu / agonists*

Substances

Analgesics
Receptors, Opioid, mu