{"doi":"10.17615/wenj-td62","title":"The G Protein-Biased  -Opioid Receptor Agonist RB-64 Is Analgesic with a Unique Spectrum of Activities In Vivo","abstract":"The hypothesis that functionally selective G protein-coupled receptor (GPCR) agonists may have enhanced therapeutic benefits has revitalized interest for many GPCR targets. In particular, although κ-opioid receptor (KOR) agonists are analgesic with a low risk of dependence and abuse, their use is limited by a propensity to induce sedation, motor incoordination, hallucinations, and dysphoria-like states. Several laboratories have produced a body of work suggesting that G protein-biased KOR agonists might be analgesic with fewer side effects. Although that has been an intriguing hypothesis, suitable KOR-selective and G protein-biased agonists have not been available to test this idea. Here we provide data using a G protein-biased agonist, RB-64 (22-thiocyanatosalvinorin A), which suggests that KOR-mediated G protein signaling induces analgesia and aversion, whereas β-arrestin-2 signaling may be associated with motor incoordination. Additionally, unlike unbiased KOR agonists, the G protein-biased ligand RB-64 does not induce sedation and does not have anhedonia-like actions, suggesting that a mechanism other than G protein signaling mediates these effects. Our findings provide the first evidence for a highly selective and G protein-biased tool compound for which many, but not all, of the negative side effects of KOR agonists can be minimized by creating G protein-biased KOR agonists.","journal":"UNC Libraries","year":2020,"id":116204,"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":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9598,"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":544660,"name":"D. E. Nichols","orcid":null,"position":1,"is_corresponding":false},{"id":544661,"name":"J. E. Robinson","orcid":null,"position":2,"is_corresponding":false},{"id":544662,"name":"Prabhakar R. Polepally","orcid":null,"position":3,"is_corresponding":false},{"id":396199,"name":"B. L. Roth","orcid":null,"position":4,"is_corresponding":false},{"id":10794,"name":"H. Zhu","orcid":"0000-0001-8066-7048","position":5,"is_corresponding":false},{"id":544663,"name":"J. K. Zjawiony","orcid":null,"position":6,"is_corresponding":false},{"id":544664,"name":"K. L. White","orcid":null,"position":7,"is_corresponding":false},{"id":544665,"name":"C. J. Malanga","orcid":null,"position":8,"is_corresponding":false},{"id":544659,"name":"J. F. DiBerto","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:13:44.286758Z","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":[]}