{"doi":"10.1021/acsptsci.5c00299","title":"P2Y<sub>14</sub> Receptor Antagonists: Piperidine Bioisosteres and Mutagenesis-Supported Molecular Modeling","abstract":"High Resolution Image Download MS PowerPoint Slide The human P2Y 14 receptor (hP2Y 14 R) has emerged as a promising target for inflammation and pain treatment, but its zwitterionic antagonists have low bioavailability. We extended the naphthalene-based antagonist series’ structure–activity relationship (SAR) by replacing an outward-facing piperidine moiety with small heteroaromatics. Notably, C -linked 1,2,3-triazol-4-yl ( 10, MRS4916) and pyrazol-3-yl ( 11, MRS4917) substitutions yielded antagonists with IC 50 values of 3.69 and 2.88 nM, respectively. In contrast, incorporation of a second triazole in the phenyl-triazolyl series ( 16 ) significantly reduced affinity. Charged phosphate groups were strategically placed at two positions of potent triazole derivative 7 to explore the ligand’s binding site vicinity and detect potential proximity to cationic side chains but neither increased affinity. Site-directed mutagenesis was used to probe the antagonist binding site vicinity. However, residues that were previously predicted to participate in the binding of antagonist 1 were found to be nonessential. Molecular dynamics based on SAR and mutagenesis identified a critical interaction between the ligand’s carboxylate and R253, defining a binding pose where the aromatic core inserts into a hydrophobic cleft between TM6 and TM7. This interaction supports a minimally orthosteric antagonist mechanism. Compound 11 demonstrated oral efficacy in reversing mechanoallodynia in mice. Additionally, a selective P2Y 14 R agonist, 2-thiouridine-5′- O -(α,β-methylene)diphosphate (MRS2905), caused acute hypothermia in mice, likely via mast cell activation, while antagonists 1 and 11 had no such effect. Our study refines the P2Y 14 R antagonist binding model and introduces new drug-like scaffolds with improved solubility and CNS penetration. This work provides a platform for future SAR optimization and virtual screening campaigns targeting P2Y 14 R.","journal":"ACS Pharmacology & Translational Science","year":2025,"id":542163,"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":0.9535,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":476636,"name":"Zhiwei Wen","orcid":"0000-0002-0821-1369","position":1,"is_corresponding":false},{"id":1225069,"name":"Matteo Pavan","orcid":"0000-0001-6234-5934","position":2,"is_corresponding":false},{"id":1431275,"name":"Siva Hariprasad Kurma","orcid":"0000-0002-6597-192X","position":3,"is_corresponding":false},{"id":476637,"name":"Tadeusz Karcz","orcid":"0000-0003-4035-659X","position":4,"is_corresponding":false},{"id":908359,"name":"Sarah A. 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Kousouros","orcid":"0000-0003-4878-4687","position":15,"is_corresponding":false},{"id":504396,"name":"Zhan-Guo Gao","orcid":"0009-0006-4777-8647","position":16,"is_corresponding":false},{"id":613043,"name":"Jonathan F. Fay","orcid":"0000-0003-1822-2384","position":17,"is_corresponding":false},{"id":233845,"name":"Kenneth A. Jacobson","orcid":"0000-0001-8104-1493","position":18,"is_corresponding":false},{"id":874585,"name":"Asmita Pramanik","orcid":null,"position":0,"is_corresponding":true}],"reference_count":93,"raw_metadata":null,"created_at":"2026-07-19T02:52:55.809501Z","pmid":"40969903","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":[]}