{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,26]],"date-time":"2026-04-26T02:26:12Z","timestamp":1777170372196,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T00:00:00Z","timestamp":1675814400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001691","name":"JSPS","doi-asserted-by":"publisher","award":["21K06814"],"award-info":[{"award-number":["21K06814"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS","doi-asserted-by":"publisher","award":["21H03028"],"award-info":[{"award-number":["21H03028"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"JSPS","doi-asserted-by":"publisher","award":["22H04922 [AdAMS]"],"award-info":[{"award-number":["22H04922 [AdAMS]"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"name":"UBE Corporation","award":["21K06814"],"award-info":[{"award-number":["21K06814"]}]},{"name":"UBE Corporation","award":["21H03028"],"award-info":[{"award-number":["21H03028"]}]},{"name":"UBE Corporation","award":["22H04922 [AdAMS]"],"award-info":[{"award-number":["22H04922 [AdAMS]"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>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 \u03bc-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 \u03b4-opioid, \u03ba-opioid, and nociceptin receptors (Ki = 1800, 460, and 1800 nM, respectively) in competitive binding assays. The [35S]-GTP\u03b3S 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.<\/jats:p>","DOI":"10.3390\/ijms24043351","type":"journal-article","created":{"date-parts":[[2023,2,8]],"date-time":"2023-02-08T03:01:45Z","timestamp":1675825305000},"page":"3351","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Inhibitory Effects of a Novel \u03bc-Opioid Receptor Nonpeptide Antagonist, UD-030, on Morphine-Induced Conditioned Place Preference"],"prefix":"10.3390","volume":"24","author":[{"given":"Soichiro","family":"Ide","sequence":"first","affiliation":[{"name":"Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noriaki","family":"Iwase","sequence":"additional","affiliation":[{"name":"UBE Corporation, Yamaguchi 755-8633, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenichi","family":"Arai","sequence":"additional","affiliation":[{"name":"UBE Corporation, Yamaguchi 755-8633, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masahiro","family":"Kojima","sequence":"additional","affiliation":[{"name":"UBE Corporation, Yamaguchi 755-8633, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigeru","family":"Ushiyama","sequence":"additional","affiliation":[{"name":"UBE Corporation, Yamaguchi 755-8633, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kaori","family":"Taniko","sequence":"additional","affiliation":[{"name":"Sanwa Kagaku Kenkyusho Co., Ltd., Aichi 461-8631, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8342-0278","authenticated-orcid":false,"given":"Kazutaka","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Tokyo 156-8506, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,8]]},"reference":[{"key":"ref_1","unstructured":"WHO (2021). World Drug Report 2021, WHO."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1093\/bja\/aer115","article-title":"Opioid receptor subtypes: Fact or artifact?","volume":"107","author":"Dietis","year":"2011","journal-title":"Br. J. Anaesth."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1798","DOI":"10.1021\/jacs.8b09756","article-title":"Chemical Interventions for the Opioid Crisis: Key Advances and Remaining Challenges","volume":"141","author":"Olson","year":"2019","journal-title":"J. Am. Chem. Soc."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"395","DOI":"10.2174\/1570159043359477","article-title":"Buprenorphine: A unique drug with complex pharmacology","volume":"2","author":"Lutfy","year":"2004","journal-title":"Curr. Neuropharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1544","DOI":"10.1073\/pnas.94.4.1544","article-title":"Opiate receptor knockout mice define mu receptor roles in endogenous nociceptive responses and morphine-induced analgesia","volume":"94","author":"Sora","year":"1997","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1016\/S0301-0082(02)00008-4","article-title":"Exploring the opioid system by gene knockout","volume":"66","author":"Kieffer","year":"2002","journal-title":"Prog. Neurobiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1182","DOI":"10.1016\/j.neuropharm.2008.03.008","article-title":"Abolished thermal and mechanical antinociception but retained visceral chemical antinociception induced by butorphanol in mu-opioid receptor knockout mice","volume":"54","author":"Ide","year":"2008","journal-title":"Neuropharmacology"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/1744-8069-7-23","article-title":"(-)-Pentazocine induces visceral chemical antinociception, but not thermal, mechanical, or somatic chemical antinociception, in mu-opioid receptor knockout mice","volume":"7","author":"Ide","year":"2011","journal-title":"Mol. Pain"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1038\/sj.npp.1300463","article-title":"Buprenorphine antinociception is abolished, but naloxone-sensitive reward is retained, in mu-opioid receptor knockout mice","volume":"29","author":"Ide","year":"2004","journal-title":"Neuropsychopharmacology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1002\/phar.2676","article-title":"Buprenorphine initiation strategies for opioid use disorder and pain management: A systematic review","volume":"42","author":"Spreen","year":"2022","journal-title":"Pharmacotherapy"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1021\/jm9900218","article-title":"Opiate aromatic pharmacophore structure-activity relationships in CTAP analogues determined by topographical bias, two-dimensional NMR, and biological activity assays","volume":"43","author":"Bonner","year":"2000","journal-title":"J. Med. Chem."},{"key":"ref_12","first-page":"544","article-title":"Novel peptidic mu opioid antagonists: Pharmacologic characterization in vitro and in vivo","volume":"249","author":"Kramer","year":"1989","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2370","DOI":"10.1021\/jm00161a037","article-title":"Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for mu opioid receptors","volume":"29","author":"Pelton","year":"1986","journal-title":"J. Med. Chem."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1021\/jm061327z","article-title":"Pharmacological properties of bivalent ligands containing butorphan linked to nalbuphine, naltrexone, and naloxone at mu, delta, and kappa opioid receptors","volume":"50","author":"Peng","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1007\/s002130050815","article-title":"Effects of test conditions on the outcome of place conditioning with morphine and naltrexone in mice","volume":"141","author":"Bespalov","year":"1999","journal-title":"Psychopharmacology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/sj.npp.1300782","article-title":"Constitutively active mu opioid receptors mediate the enhanced conditioned aversive effect of naloxone in morphine-dependent mice","volume":"31","author":"Shoblock","year":"2006","journal-title":"Neuropsychopharmacology"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"715","DOI":"10.1056\/NEJMct0801733","article-title":"Naltrexone for the management of alcohol dependence","volume":"359","author":"Anton","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.brainresbull.2005.05.028","article-title":"Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone","volume":"67","author":"Chiu","year":"2005","journal-title":"Brain Res. Bull."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"2347","DOI":"10.1038\/npp.2015.83","article-title":"The effects of naltrexone on subjective response to methamphetamine in a clinical sample: A double-blind, placebo-controlled laboratory study","volume":"40","author":"Ray","year":"2015","journal-title":"Neuropsychopharmacology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Al-Eitan, L.N., Rababa\u2019h, D.M., and Alghamdi, M.A. (2021). Genetic susceptibility of opioid receptor genes polymorphism to drug addiction: A candidate-gene association study. BMC Psychiatry, 21.","DOI":"10.1186\/s12888-020-03006-z"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/sj.npp.1300598","article-title":"Increased attributable risk related to a functional mu-opioid receptor gene polymorphism in association with alcohol dependence in central Sweden","volume":"30","author":"Bart","year":"2005","journal-title":"Neuropsychopharmacology"},{"key":"ref_22","first-page":"179","article-title":"Linkage disequilibrium and association with methamphetamine dependence\/psychosis of mu-opioid receptor gene polymorphisms","volume":"6","author":"Ide","year":"2006","journal-title":"Pharm. J."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/S0376-8716(99)00033-2","article-title":"Naltrexone shortened opioid detoxification with buprenorphine","volume":"56","author":"Umbricht","year":"1999","journal-title":"Drug Alcohol Depend."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2107","DOI":"10.1016\/j.bmcl.2005.02.032","article-title":"Synthesis and opioid receptor binding properties of a highly potent 4-hydroxy analogue of naltrexone","volume":"15","author":"Wentland","year":"2005","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_25","first-page":"49","article-title":"Methylnaltrexone in the treatment of opioid-induced constipation","volume":"1","author":"Standifer","year":"2008","journal-title":"Clin. Exp. Gastroenterol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2332","DOI":"10.1056\/NEJMoa0707377","article-title":"Methylnaltrexone for opioid-induced constipation in advanced illness","volume":"358","author":"Thomas","year":"2008","journal-title":"N. Engl. J. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1941","DOI":"10.1016\/j.euroneuro.2016.10.008","article-title":"Nalmefene for the management of alcohol dependence: Review on its pharmacology, mechanism of action and meta-analysis on its clinical efficacy","volume":"26","author":"Mann","year":"2016","journal-title":"Eur. Neuropsychopharmacol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1016\/0014-2999(81)90355-1","article-title":"The irreversible narcotic antagonistic and reversible agonistic properties of the fumaramate methyl ester derivative of naltrexone","volume":"70","author":"Takemori","year":"1981","journal-title":"Eur. J. Pharmacol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1016\/j.drudis.2017.07.002","article-title":"Mu-Opioid receptor biased ligands: A safer and painless discovery of analgesics?","volume":"22","author":"Li","year":"2017","journal-title":"Drug Discov. Today"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/bs.irn.2017.08.001","article-title":"Dynorphin\/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction","volume":"136","author":"Karkhanis","year":"2017","journal-title":"Int. Rev. Neurobiol."},{"key":"ref_31","unstructured":"Jimenez-Fernandez, B., Calomarde-Gomez, C., Lopez-Lazcano, A., Lligona, A., Gual, A., and Lopez-Pelayo, H. (2022). Systematic review on the clinical management of chronic pain and comorbid opioid use disorder. Adicciones, 1680."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1186\/s13011-022-00464-4","article-title":"Developing a novel treatment for patients with chronic pain and Opioid User Disorder","volume":"17","author":"Wachholtz","year":"2022","journal-title":"Subst. Abuse Treat. Prev. Policy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/S0301-0082(98)00060-4","article-title":"Measuring reward with the conditioned place preference paradigm: A comprehensive review of drug effects, recent progress and new issues","volume":"56","author":"Tzschentke","year":"1998","journal-title":"Prog. Neurobiol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3351\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:27:38Z","timestamp":1760120858000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/24\/4\/3351"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,8]]},"references-count":33,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["ijms24043351"],"URL":"https:\/\/doi.org\/10.3390\/ijms24043351","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,8]]}}}