{"doi":"10.17615/9vwt-ya70","title":"Pyrimidine Ribonucleotides with Enhanced Selectivity as P2Y 6 Receptor Agonists: Novel 4-Alkyloxyimino, (S)-Methanocarba, and 5′-Triphosphate γ-Ester Modifications †","abstract":"The P2Y6 receptor is a cytoprotective G protein-coupled receptor (GPCR) activated by UDP (EC50, 0.30 μM). We compared and combined modifications to enhance P2Y6 receptor agonist selectivity, including ribose ring constraint, 5-iodo and 4-alkyloxyimino modifications, and phosphate modifications such as α,β-methylene and extension of the terminal phosphate group into γ-esters of UTP analogues. The conformationally constrained (S)-methanocarba UDP is a full agonist (EC50 0.042 μM). 4-Methoxyimino modification of pyrimidine enhanced P2Y6, preserved P2Y2 and P2Y4, and abolished P2Y14 receptor potency, in the appropriate nucleotide. N4-Benzyloxy-CDP (15, MRS2964) and N4-methoxy-Cp3U (23, MRS2957) were potent, selective P2Y6 receptor agonists (EC50 0.026 μM and 0.012 μM, respectively). A hydrophobic binding region near the nucleobase was explored with receptor modeling and docking. UTP-γ-aryl and cycloalkyl phosphoesters displayed only intermediate P2Y6 receptor potency, but had enhanced stability in acid and cell membranes. UTP-glucose was inactive, but its (S)-methanocarba analogue and N4-methoxy-cytidine 5′-triphospho-γ-[1]glucose were active (EC50 of 2.47 μM and 0.18 μM, respectively). Thus, the potency, selectivity, and stability of pyrimidine nucleotides as P2Y6 receptor agonists may be enhanced by modest structural changes.","journal":"UNC Libraries","year":2020,"id":141516,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9493,"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":411440,"name":"Barkın Berk","orcid":"0000-0001-6047-2796","position":1,"is_corresponding":false},{"id":233845,"name":"Kenneth A. Jacobson","orcid":"0000-0001-8104-1493","position":2,"is_corresponding":false},{"id":607017,"name":"Рамачандран Баласубраманиан","orcid":"0000-0002-6345-0127","position":3,"is_corresponding":false},{"id":395042,"name":"Dilip K. Tosh","orcid":"0000-0003-0932-4143","position":4,"is_corresponding":false},{"id":547602,"name":"Hiroshi Maruoka","orcid":null,"position":5,"is_corresponding":false},{"id":515149,"name":"Stefano Costanzi","orcid":"0000-0003-3183-7332","position":6,"is_corresponding":false},{"id":607559,"name":"Lauren E. Burianek","orcid":null,"position":7,"is_corresponding":false},{"id":546799,"name":"Matthew O. Barrett","orcid":"0000-0001-7851-0308","position":8,"is_corresponding":false},{"id":500684,"name":"Artem Melman","orcid":"0000-0003-1152-972X","position":9,"is_corresponding":false},{"id":515146,"name":"Hyojin Ko","orcid":"0000-0002-1216-0066","position":10,"is_corresponding":false},{"id":515775,"name":"T. Kendall Harden","orcid":null,"position":0,"is_corresponding":true}],"reference_count":0,"raw_metadata":null,"created_at":"2026-07-18T23:17:24.429854Z","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":[]}