Developing the Dopamine D3 Receptor (D3R) Antagonist, (R)-VK4-116, as a Non-Opioid Medication for the Treatment of...

Opioid use disorder (OUD) remains a major global health challenge, and currently approved treatments (methadone, buprenorphine, and naltrexone) are all opioid receptor-targeting 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-opioid therapeutics for substance use disorders, including D3R-selective compounds that have advanced into clinical development. We then present VK4-116 as a representative case study of translational progress in this field. Guided by D3R crystal structure-based modeling and medicinal chemistry optimization, VK4-116 was identified as a highly D3R-selective antagonist with favorable brain penetration and in vivo activity. In rodent models, VK4-116 reduced opioid self-administration, drug seeking, withdrawal-induced hyperalgesia, and irritability-like behavior, while enhancing opioid analgesia and reversing cocaine-induced cognitive deficits. The eutomer, (R)-VK4-116, was advanced through preclinical development, including scalable good manufacturing practices-compatible synthesis, formulation optimization to improve oral bioavailability, and investigational new drug-enabling toxicology studies defining toxicity endpoints, the no observed adverse effect level, and a safe clinical starting dose. Together, these findings support clinical evaluation of (R)-VK4-116 and illustrate the therapeutic promise of D3R antagonists for OUD and polysubstance use disorders.