{"doi":"10.1021/acsptsci.3c00126","title":"First Potent Macrocyclic A<sub>3</sub> Adenosine Receptor Agonists Reveal G-Protein and β-Arrestin2 Signaling Preferences","abstract":"( N )-Methanocarba adenosine derivatives (A 3 adenosine receptor (AR) agonists containing bicyclo[3.1.0]hexane replacing furanose) were chain-extended at N 6 and C2 positions with terminal alkenes for ring closure. The resulting macrocycles of 17–20 atoms retained affinity, indicating a spatially proximal orientation of these receptor-bound chains, consistent with molecular modeling of 12 . C2-Arylethynyl-linked macrocycle 19 was more A 3 AR-selective than 2-ether-linked macrocycle 12 (both 5′-methylamides, human (h) A 3 AR affinities ( K i ): 22.1 and 25.8 nM, respectively), with lower mouse A 3 AR affinities. Functional hA 3 AR comparison of two sets of open/closed analogues in β-arrestin2 and G i/o protein assays showed certain signaling preferences divergent from reference agonist Cl-IB-MECA 1 . The potencies of 1 at all three Gα i isoforms were slightly less than its hA 3 AR binding affinity ( K i: 1.4 nM), while the Gα i1 and Gα i2 potencies of macrocycle 12 were roughly an order of magnitude higher than its radioligand binding affinity. Gα i2 -coupling was enhanced in macrocycle 12 (EC 50 2.56 nM, ∼40% greater maximal efficacy than 1 ). Di-O-allyl precursor 18 cyclized to form 19, increasing the Gα i1 potency by 7.5-fold. The macrocycles 12 and 19 and their open precursors 11 and 18 potently stimulated β-arrestin2 recruitment, with EC 50 values (nM) of 5.17, 4.36, 1.30, and 4.35, respectively, and with nearly 50% greater efficacy compared to 1 . This example of macrocyclization altering the coupling pathways of small-molecule (nonpeptide) GPCR agonists is the first for potent and selective macrocyclic AR agonists. These initial macrocyclic derivatives can serve as a guide for the future design of macrocyclic AR agonists displaying unanticipated pharmacology.","journal":"ACS Pharmacology & Translational Science","year":2023,"id":375294,"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":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9538,"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":400012,"name":"Courtney Fisher","orcid":"0000-0003-2089-9116","position":1,"is_corresponding":false},{"id":392354,"name":"Veronica Salmaso","orcid":"0000-0001-5305-8351","position":2,"is_corresponding":false},{"id":382798,"name":"Tina C. Wan","orcid":"0000-0001-6643-4678","position":3,"is_corresponding":false},{"id":396300,"name":"Ryan G. Campbell","orcid":null,"position":4,"is_corresponding":false},{"id":402651,"name":"Eric Chen","orcid":"0000-0002-5247-3593","position":5,"is_corresponding":false},{"id":275808,"name":"Zhan‐Guo Gao","orcid":"0000-0002-6663-524X","position":6,"is_corresponding":false},{"id":382799,"name":"John A. Auchampach","orcid":"0000-0002-8005-4599","position":7,"is_corresponding":false},{"id":233845,"name":"Kenneth A. Jacobson","orcid":"0000-0001-8104-1493","position":8,"is_corresponding":false},{"id":395042,"name":"Dilip K. Tosh","orcid":"0000-0003-0932-4143","position":0,"is_corresponding":true}],"reference_count":77,"raw_metadata":null,"created_at":"2026-07-19T01:16:19.336238Z","pmid":"37705595","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":[]}