{"doi":"10.1073/pnas.2302668120","title":"Identification of a β-arrestin-biased negative allosteric modulator for the β <sub>2</sub> -adrenergic receptor","abstract":"Catecholamine-stimulated β 2 -adrenergic receptor (β 2 AR) signaling via the canonical G s –adenylyl cyclase–cAMP–PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous β-agonists in the treatment of airway disease. β 2 AR signaling is tightly regulated by GRKs and β-arrestins, which together promote β 2 AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias β 2 AR signaling toward the G s pathway while avoiding β-arrestin-mediated effects may provide a strategy to improve the functional consequences of β 2 AR activation. Since attempts to develop G s -biased agonists and allosteric modulators for the β 2 AR have been largely unsuccessful, here we screened small molecule libraries for allosteric modulators that selectively inhibit β-arrestin recruitment to the receptor. This screen identified several compounds that met this profile, and, of these, a difluorophenyl quinazoline (DFPQ) derivative was found to be a selective negative allosteric modulator of β-arrestin recruitment to the β 2 AR while having no effect on β 2 AR coupling to G s . DFPQ effectively inhibits agonist-promoted phosphorylation and internalization of the β 2 AR and protects against the functional desensitization of β-agonist mediated regulation in cell and tissue models. The effects of DFPQ were also specific to the β 2 AR with minimal effects on the β 1 AR. Modeling, mutagenesis, and medicinal chemistry studies support DFPQ derivatives binding to an intracellular membrane-facing region of the β 2 AR, including residues within transmembrane domains 3 and 4 and intracellular loop 2. DFPQ thus represents a class of biased allosteric modulators that targets an allosteric site of the β 2 AR.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":336447,"datarank":0.4493598410330987,"base_score":2.995732273553991,"endowment":2.995732273553991,"self_citation_contribution":0.4493598410330987,"citation_network_contribution":0.0,"self_endowment_contribution":0.4493598410330987,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":19,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9592,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":738829,"name":"Francesco De Pascali","orcid":"0000-0002-5880-3725","position":1,"is_corresponding":false},{"id":1002754,"name":"Nathan Hopfinger","orcid":null,"position":2,"is_corresponding":false},{"id":339926,"name":"Konstantin E. Komolov","orcid":"0000-0001-6799-4626","position":3,"is_corresponding":false},{"id":340948,"name":"Daniela K. Laurinavichyute","orcid":null,"position":4,"is_corresponding":false},{"id":349657,"name":"Poli Adi Narayana Reddy","orcid":null,"position":5,"is_corresponding":false},{"id":1066873,"name":"Leon A. Sakkal","orcid":"0000-0002-8164-6772","position":6,"is_corresponding":false},{"id":1067311,"name":"Kyle Z. Rajkowski","orcid":null,"position":7,"is_corresponding":false},{"id":373524,"name":"Ajay P. Nayak","orcid":"0000-0003-3437-0096","position":8,"is_corresponding":false},{"id":1066874,"name":"Justin B. Lee","orcid":"0000-0002-3153-3075","position":9,"is_corresponding":false},{"id":937923,"name":"Jordan Lee","orcid":"0000-0002-6489-8636","position":10,"is_corresponding":false},{"id":435588,"name":"Gaoyuan Cao","orcid":"0000-0001-8308-7401","position":11,"is_corresponding":false},{"id":597273,"name":"Preston S. Donover","orcid":"0009-0003-5627-0560","position":12,"is_corresponding":false},{"id":1066875,"name":"Melvin Reichman","orcid":"0000-0001-8833-3421","position":13,"is_corresponding":false},{"id":452785,"name":"Steven S. An","orcid":"0000-0003-4723-1888","position":14,"is_corresponding":false},{"id":348575,"name":"Joseph M. Salvino","orcid":"0000-0002-2184-5980","position":15,"is_corresponding":false},{"id":409183,"name":"Raymond B. Penn","orcid":"0000-0001-8452-5880","position":16,"is_corresponding":false},{"id":517711,"name":"Roger S. Armen","orcid":"0000-0003-3830-1450","position":17,"is_corresponding":false},{"id":1066876,"name":"Charles P. Scott","orcid":"0000-0002-3191-4839","position":18,"is_corresponding":false},{"id":315488,"name":"Jeffrey Benovic","orcid":"0000-0001-5705-7129","position":19,"is_corresponding":false},{"id":315487,"name":"Michael Ippolito","orcid":"0000-0001-5881-4910","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:10:17.243221Z","pmid":"37490535","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":[]}