Inhibitory Effects of a Novel μ-Opioid Receptor Nonpeptide Antagonist, UD-030, on Morphine-Induced Conditioned Place Preference

Author:

Ide Soichiro1,Iwase Noriaki2,Arai Kenichi2,Kojima Masahiro2,Ushiyama Shigeru2,Taniko Kaori3,Ikeda Kazutaka1ORCID

Affiliation:

1. Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan

2. UBE Corporation, Yamaguchi 755-8633, Japan

3. Sanwa Kagaku Kenkyusho Co., Ltd., Aichi 461-8631, Japan

Abstract

Although opioids are widely used to treat moderate to severe pain, opioid addiction and the opioid overdose epidemic are becoming more serious. Although opioid receptor antagonists/partial agonists, such as naltrexone and buprenorphine, have relatively low selectivity for the μ-opioid receptor (MOP), they have been used for the management of opioid use disorder. The utility of highly selective MOP antagonists remains to be evaluated. Here, we biologically and pharmacologically evaluated a novel nonpeptide ligand, UD-030, as a selective MOP antagonist. UD-030 had more than 100-fold higher binding affinity for the human MOP (Ki = 3.1 nM) than for δ-opioid, κ-opioid, and nociceptin receptors (Ki = 1800, 460, and 1800 nM, respectively) in competitive binding assays. The [35S]-GTPγS binding assay showed that UD-030 acts as a selective MOP full antagonist. The oral administration of UD-030 dose-dependently suppressed the acquisition and expression of morphine-induced conditioned place preference in C57BL/6J mice, and its effects were comparable to naltrexone. These results indicate the UD-030 may be a new candidate for the treatment of opioid use disorder, with characteristics that differ from traditional medications that are in clinical use.

Funder

JSPS

UBE Corporation

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference33 articles.

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