{"doi":"10.17615/1mm3-wd36","title":"Discovery of β-arrestin-biased dopamine D 2 ligands for probing signal transduction pathways essential for antipsychotic efficacy","abstract":"Elucidating the key signal transduction pathways essential for both antipsychotic efficacy and side-effect profiles is essential for developing safer and more effective therapies. Recent work has highlighted noncanonical modes of dopamine D 2 receptor (D 2R) signaling via β-arrestins as being important for the therapeutic actions of both antipsychotic and antimanic agents. We thus sought to create unique D 2R agonists that display signaling bias via β-arrestinergic signaling. Through a robust diversity-oriented modification of the scaffold represented by aripiprazole (1), we discovered UNC9975 (2), UNC0006 (3), and UNC9994 (4) as unprecedented β-arrestin-biased D 2R ligands. These compounds also represent unprecedented β-arrestin-biased ligands for a G i-coupled G protein-coupled receptor (GPCR). Significantly, UNC9975, UNC0006, and UNC9994 are simultaneously antagonists of G i-regulated cAMP production and partial agonists for D 2R/β-arrestin-2 interactions. Importantly, UNC9975 displayed potent antipsychotic-like activity without inducing motoric side effects in inbred C57BL/6 mice in vivo. Genetic deletion of β-arrestin-2 simultaneously attenuated the antipsychotic actions of UNC9975 and transformed it into a typical antipsychotic drug with a high propensity to induce catalepsy. Similarly, the antipsychotic-like activity displayed by UNC9994, an extremely β-arrestin-biased D 2R agonist, in wild-type mice was completely abolished in β-arrestin-2 knockout mice. Taken together, our results suggest that β-arrestin signaling and recruitment can be simultaneously a significant contributor to antipsychotic efficacy and protective against motoric side effects. These functionally selective, β-arrestin-biased D 2R ligands represent valuable chemical probes for further investigations of D 2R signaling in health and disease.","journal":"UNC Libraries","year":2020,"id":115238,"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":0.9582,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2020-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":396552,"name":"B.L. Roth","orcid":null,"position":1,"is_corresponding":false},{"id":541503,"name":"N.H. Jensen","orcid":null,"position":2,"is_corresponding":false},{"id":515753,"name":"M.F. Sassano","orcid":null,"position":3,"is_corresponding":false},{"id":541504,"name":"M.G. Caron","orcid":null,"position":4,"is_corresponding":false},{"id":540199,"name":"X. Bai","orcid":null,"position":5,"is_corresponding":false},{"id":515757,"name":"V. Setola","orcid":null,"position":6,"is_corresponding":false},{"id":541505,"name":"W.C. Wetsel","orcid":null,"position":7,"is_corresponding":false},{"id":396555,"name":"J. Jin","orcid":null,"position":8,"is_corresponding":false},{"id":541506,"name":"J.M. Yost","orcid":null,"position":9,"is_corresponding":false},{"id":541507,"name":"J.A. Javitch","orcid":null,"position":10,"is_corresponding":false},{"id":8412,"name":"X. Chen","orcid":"0009-0000-5088-114X","position":11,"is_corresponding":false},{"id":540197,"name":"Baihe Feng","orcid":null,"position":12,"is_corresponding":false},{"id":539386,"name":"Sydney J Peterson","orcid":"0009-0008-4605-6698","position":13,"is_corresponding":false},{"id":541508,"name":"P.N. Yadav","orcid":null,"position":14,"is_corresponding":false},{"id":540203,"name":"Xinmeng Che","orcid":null,"position":15,"is_corresponding":false},{"id":24625,"name":"M. Chen","orcid":"0000-0001-7021-3720","position":16,"is_corresponding":false},{"id":541509,"name":"J.A. Allen","orcid":null,"position":17,"is_corresponding":false},{"id":541510,"name":"S.V. Frye","orcid":null,"position":18,"is_corresponding":false},{"id":396197,"name":"X.-P. Huang","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:13:36.820928Z","pmid":null,"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":[]}