{"doi":"10.1021/acsptsci.4c00223","title":"2-Substituted (N)-Methanocarba A<sub>3</sub> Adenosine Receptor Agonists: In Silico, In Vitro, and In Vivo Characterization","abstract":"High Resolution Image Download MS PowerPoint Slide 2-Arylethynyl (N)-methanocarba adenosine 5′-methylamides are selective A 3 adenosine receptor (AR) agonists containing a preestablished receptor-preferred pseudoribose conformation. Here, we compare analogues having bulky 2-substitution, either containing or lacking an ethynyl spacer between adenine and a cyclic group. 2-Aryl compounds 9 – 11, 13, 14, 19, 22, 23, 27, 29, 31, and 34, lacking a spacer, had human (h) A 3 AR K i values of 2–30 nM, and others displayed lower affinity. Mouse (m) A 3 AR affinity varied, with 2-arylethynyl having a higher affinity than 2-aryl analogues ( 7, 8 > 3c, 3d > 3b ). However, 2-aryl-4′-truncated derivatives had greatly reduced hA 3 AR affinity, even containing affinity-enhancing N 6 -dopamine-derived substituents. Molecular modeling, including molecular dynamics simulation, predicted stable poses in the canonical A 3 AR agonist binding site, but 2-aryl (ECL2 interactions) and 2-arylethynyl (TM2 interactions) substituents have different conformations and environments. In a hA 3 AR miniGα i recruitment assay, 31 (MRS8062) was (slightly) more potent compared to a β-arrestin2 recruitment assay, both in engineered HEK293T cells, and its maximal efficacy ( E max ) was much higher (165%) than reference agonist NECA’s. Thus, in the 2-aryl series, A 3 AR affinity and selectivity were variable and generally reduced compared to the 2-arylethynyl series, with a greater dependence on the specific aryl group present. Selected compounds were studied in vivo in an ischemic model of peripheral artery disease (PAD). Rigidified 2-arylethynyl analogues 3a – 3c were protective in this model of skeletal muscle ischemia-reperfusion injury/claudication, as previously shown only for moderately A 3 AR-selective ribosides or (N)-methanocarba derivatives. Thus, we have expanded the A 3 AR agonist SAR for (N)-methanocarba adenosines.","journal":"ACS Pharmacology & Translational Science","year":2024,"id":453690,"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":8,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"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":1225069,"name":"Matteo Pavan","orcid":"0000-0001-6234-5934","position":1,"is_corresponding":false},{"id":283664,"name":"Chunxia Cronin","orcid":null,"position":2,"is_corresponding":false},{"id":460863,"name":"Eline Pottie","orcid":"0000-0002-9077-4055","position":3,"is_corresponding":false},{"id":382798,"name":"Tina C. Wan","orcid":"0000-0001-6643-4678","position":4,"is_corresponding":false},{"id":402651,"name":"Eric Chen","orcid":"0000-0002-5247-3593","position":5,"is_corresponding":false},{"id":908359,"name":"Sarah A. Lewicki","orcid":"0009-0008-7449-5065","position":6,"is_corresponding":false},{"id":396300,"name":"Ryan G. Campbell","orcid":null,"position":7,"is_corresponding":false},{"id":504396,"name":"Zhan-Guo Gao","orcid":"0009-0006-4777-8647","position":8,"is_corresponding":false},{"id":382799,"name":"John A. Auchampach","orcid":"0000-0002-8005-4599","position":9,"is_corresponding":false},{"id":460864,"name":"Christophe P. Stove","orcid":"0000-0001-7126-348X","position":10,"is_corresponding":false},{"id":282334,"name":"Bruce T. Liang","orcid":"0000-0002-4444-387X","position":11,"is_corresponding":false},{"id":233845,"name":"Kenneth A. Jacobson","orcid":"0000-0001-8104-1493","position":12,"is_corresponding":false},{"id":395042,"name":"Dilip K. Tosh","orcid":"0000-0003-0932-4143","position":0,"is_corresponding":true}],"reference_count":74,"raw_metadata":null,"created_at":"2026-07-19T02:03:03.428151Z","pmid":"39022354","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":[]}