{"doi":"10.1371/journal.pone.0315569","title":"In vitro safety evaluation of dopamine D3R antagonist, R-VK4-116, as a potential medication for the treatment of opioid use disorder","abstract":"R-VK4-116 is currently being developed as a medication to treat opioid use disorder (OUD). To characterize in vitro safety properties of R-VK4-116, metabolic stability in hepatocytes or liver microsomes, metabolite identification, metabolism/transporter-mediated drug interactions, lysosomal perturbation, mitochondrial toxicity, off-target enzyme effects, cellular and nuclear receptor functional assays, electrophysiological assays, CiPA, KINOMEscanTM, plasma protein binding, phospholipidosis and steatosis assays were performed. Overall, R-VK4-116 was metabolically stable in hepatocytes and microsomes. Four major metabolites were detected: two mono-oxidation products, one di-oxidation product, and one demethylated plus di-oxidation product. CYP2D6 and CYP3A4 were major contributors in R-VK4-116 metabolism. Further, R-VK4-116 did not induce/inhibit CYP enzymes. However, R-VK4-116 inhibited BCRP/P-gp, and showed antagonist effects on α1A(h), H1(h) and agonist effect on hGABAA∞1β2γ2 at 10 μM. R-VK4-116 inhibited hERG and Kir2.1 at a high concentration of 100 μM. KINOMEscanTM provided 5 hits (CHEK2, HPK1, MARK3, SRPK2 and TNK1) with Kds of >10 μM. Further, R-VK4-116 was bound to human, rat and dog plasma proteins (~83-93%). R-VK4-116 did not induce lysosome perturbation, mitochondrial toxicity, phospholipidosis, or steatosis at ≤10 μM. These results demonstrated that R-VK4-116 possesses favorable in vitro safety properties and supports further development as a potential medication for OUD.","journal":"PLoS ONE","year":2024,"id":452073,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":3,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9574,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":348848,"name":"Amy Hauck Newman","orcid":"0000-0001-9065-4072","position":1,"is_corresponding":false},{"id":326238,"name":"Pramod Terse","orcid":"0000-0002-3343-3342","position":2,"is_corresponding":false},{"id":250678,"name":"Rahul Nandre","orcid":"0000-0002-0828-0970","position":0,"is_corresponding":true}],"reference_count":55,"raw_metadata":null,"created_at":"2026-07-19T02:02:50.407779Z","pmid":"39680602","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}