{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T16:24:48Z","timestamp":1787675088237,"version":"build-2784847793"},"reference-count":129,"publisher":"Wiley","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Medicinal Research Reviews"],"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Opioid use disorder (OUD) remains a major global health challenge, and currently approved treatments (methadone, buprenorphine, and naltrexone) are all opioid receptor\u2010targeting drugs with limitations in access, adherence, stigma, and use in polysubstance use disorders. Because the dopamine D3 receptor (D3R) is enriched in limbic brain regions involved in reward, drug dependence, and impulse control, it has become an attractive target for treating OUD and related substance use disorders. This review first surveys the emerging field of D3R antagonists as non\u2010opioid therapeutics for substance use disorders, including D3R\u2010selective compounds that have advanced into clinical development. We then present VK4\u2010116 as a representative case study of translational progress in this field. Guided by D3R crystal structure\u2010based modeling and medicinal chemistry optimization, VK4\u2010116 was identified as a highly D3R\u2010selective antagonist with favorable brain penetration and in vivo activity. In rodent models, VK4\u2010116 reduced opioid self\u2010administration, drug seeking, withdrawal\u2010induced hyperalgesia, and irritability\u2010like behavior, while enhancing opioid analgesia and reversing cocaine\u2010induced cognitive deficits. The eutomer,\n                    <jats:italic>(R)<\/jats:italic>\n                    \u2010VK4\u2010116, was advanced through preclinical development, including scalable good manufacturing practices\u2010compatible synthesis, formulation optimization to improve oral bioavailability, and investigational new drug\u2010enabling toxicology studies defining toxicity endpoints, the no observed adverse effect level, and a safe clinical starting dose. Together, these findings support clinical evaluation of\n                    <jats:italic>(R)<\/jats:italic>\n                    \u2010VK4\u2010116 and illustrate the therapeutic promise of D3R antagonists for OUD and polysubstance use disorders.\n                  <\/jats:p>","DOI":"10.1002\/med.70101","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T12:59:53Z","timestamp":1787662793000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Developing the Dopamine D3 Receptor (D3R) Antagonist, (\n                    <i>R<\/i>\n                    )\u2010VK4\u2010116, as a Non\u2010Opioid Medication for the Treatment of Opioid Use Disorder"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6610-9175","authenticated-orcid":false,"given":"Chia\u2010Kuei","family":"Wu","sequence":"first","affiliation":[{"name":"Therapeutic Development Branch, Division of 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