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

Reviews To Read – August 2026

Published in Medicinal Research Reviews by Amy Newman, Scientific Director of the NIDA IRP.

NIDA-IRP Researchers are developing (R)-VK4-116 as a possible non-opioid medication for opioid use disorder. Unlike methadone, buprenorphine, and naltrexone, which act on opioid receptors, (R)-VK4-116 blocks the dopamine D3 receptor. This receptor is concentrated in brain regions involved in reward, motivation, and responses to drug-related cues, making it a potential target for reducing drug use and relapse without directly affecting opioid receptors.

Studies in rodents found that VK4-116 reduced oxycodone use and drug-seeking behavior, as well as increased pain sensitivity and irritability-like behavior during opioid withdrawal. Importantly, it did not interfere with opioids’ pain-relieving effects and may enhance them. The compound also reversed some cognitive problems caused by long-term cocaine exposure in rats and did not worsen the cardiovascular effects of oxycodone or cocaine in preclinical testing.

The more active enantiomer, (R)-VK4-116, was selected for further development. Safety studies identified doses suitable for initial testing in people and found no major safety concerns under the conditions studied. The Food and Drug Administration cleared the compound in 2025 to begin a first-in-human clinical study. Whether (R)-VK4-116 is safe and effective for treating opioid use disorder in people remains to be determined in clinical trials.

Chia-Kuei Wu; Yu-Chih Lin; Junfeng Huang; Bangwei Ding; Pramod Terse; Rahul Nandre; Haksong Jin; Molly Congdon; Kun Shen; Philip Sanderson; Gregory Tawa; Stephanie Mounaud; Marta De Santis; Donald Lo; Elizabeth A Ottinger; Amy Hauck Newman

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

In: Med Res Rev, 2026, ISSN: 1098-1128.

Abstract | Links

@article{pmid42640111,

title = {Developing the Dopamine D3 Receptor (D3R) Antagonist, (R)-VK4-116, as a Non-Opioid Medication for the Treatment of Opioid Use Disorder},

author = {Chia-Kuei Wu and Yu-Chih Lin and Junfeng Huang and Bangwei Ding and Pramod Terse and Rahul Nandre and Haksong Jin and Molly Congdon and Kun Shen and Philip Sanderson and Gregory Tawa and Stephanie Mounaud and Marta De Santis and Donald Lo and Elizabeth A Ottinger and Amy Hauck Newman},

url = {https://pubmed.ncbi.nlm.nih.gov/42640111/},

doi = {10.1002/med.70101},

issn = {1098-1128},

year  = {2026},

date = {2026-08-01},

urldate = {2026-08-01},

journal = {Med Res Rev},

abstract = {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.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}