Discovery of δ opioid receptor full agonists lacking a basic nitrogen atom and their antidepressant-like effects

Hideaki Fujii; Yota Uchida; Marie Shibasaki; Moeno Nishida; Toshinori Yoshioka; Riho Kobayashi; Ayaka Honjo; Kennosuke Itoh; Daisuke Yamada; Shigeto Hirayama; Akiyoshi Saitoh

doi:10.1016/j.bmcl.2020.127176

Discovery of δ opioid receptor full agonists lacking a basic nitrogen atom and their antidepressant-like effects

Bioorg Med Chem Lett. 2020 Jun 15;30(12):127176. doi: 10.1016/j.bmcl.2020.127176. Epub 2020 Apr 8.

Authors

Affiliations

¹ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan. Electronic address: fujiih@pharm.kitasato-u.ac.jp.
² Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.
³ Laboratory of Pharmacology, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan.
⁴ Laboratory of Medicinal Chemistry, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan; Medicinal Research Laboratories, School of Pharmacy, Kitasato University, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8641, Japan.

PMID: 32299730
DOI: 10.1016/j.bmcl.2020.127176

Abstract

We have recently reported that the elaboration of the N-substituent in the δ opioid receptor (DOR) antagonist naltrindole (NTI) enabled the regulation of the DOR activities from full inverse agonists to weak partial agonists. The investigations of amide-type NTI derivatives revealed that N-phenylacetyl and N-dihydrocinnamoyl derivatives 3a and 3b were DOR full agonists. The same transformations were applied to a DOR agonist KNT-127 to provide the more potent DOR agonists 6a and 6b. Among the tested compounds, the most efficacious compound 6a showed dose-dependent antidepressant-like effects in the mouse forced swim test. The antidepressant-like effects by 6a seemed to be more potent than those of KNT-127, which is a more potent DOR agonist in in vitro assays. The amide-type compound like 6a may more fully penetrate into the central nervous system.

Keywords: Antidepressant-like effect; DOR agonist; Indolomorphinan; Opioid; Quinolinomorphinan.

MeSH terms

Animals
Antidepressive Agents / chemical synthesis
Antidepressive Agents / chemistry
Antidepressive Agents / pharmacology*
Behavior, Animal / drug effects
Depression / drug therapy*
Dose-Response Relationship, Drug
Drug Discovery*
Mice
Molecular Structure
Receptors, Opioid, delta / agonists*
Structure-Activity Relationship

Substances

Antidepressive Agents
Receptors, Opioid, delta