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Nevertheless, gefapixant\/AF\u2010219, the only marketed P2X3 receptor antagonist, might lead taste disorders by modulating the human P2X2\/3 (hP2X2\/3) heterotrimer. Hence, in RCC drug development, compounds exhibiting strong affinity for the hP2X3 homotrimer and a weak affinity for the hP2X2\/3 heterotrimer hold promise. An example of such a molecule is sivopixant\/S\u2010600918, a clinical Phase II RCC candidate with a reduced incidence of taste disturbance compared to gefapixant. Sivopixant and its analogue, (3\u2010(4\u2010([3\u2010chloro\u20104\u2010isopropoxyphenyl]amino)\u20103\u2010(4\u2010methylbenzyl)\u20102,6\u2010dioxo\u20103,6\u2010dihydro\u20101,3,5\u2010triazin\u20101(2<jats:italic>H<\/jats:italic>)\u2010yl)propanoic acid (DDTPA), exhibit both high affinity and high selectivity for hP2X3 homotrimers, compared with hP2X2\/3 heterotrimers. The mechanism underlying the druggable site and its high selectivity remains unclear.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>To analyse mechanisms that distinguish this drug candidate from other inhibitors of the P2X3 receptors we used a combination of chimera construction, site covalent occupation, metadynamics, mutagenesis and whole\u2010cell recording.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>The high affinity and selectivity of sivopixant\/DDTPA for hP2X3 receptors was determined by the tri\u2010symmetric site located close to the upper vestibule. Substitution of only four amino acids inside the upper body domain of hP2X2 with those of hP2X3, enabled the hP2X2\/3 heterotrimer to exhibit a similar level of apparent affinity for sivopixant\/DDTPA as the hP2X3 homotrimer.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>From the receptor\u2010ligand recognition perspective, we have elucidated the molecular basis of novel RCC clinical candidates' cough\u2010suppressing properties and reduced side effects, offering a promising approach to the discovery of novel drugs that specifically target P2X3 receptors.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16273","type":"journal-article","created":{"date-parts":[[2023,11,3]],"date-time":"2023-11-03T11:14:07Z","timestamp":1699010047000},"page":"1203-1220","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Druggable site near the upper vestibule determines the high affinity and P2X3 homotrimer selectivity of sivopixant\/S\u2010600918 and its analogue DDTPA"],"prefix":"10.1111","volume":"181","author":[{"given":"Dong\u2010Ping","family":"Wang","sequence":"first","affiliation":[{"name":"College of Bioscience and Biotechnology Hunan Agricultural University  Changsha China"},{"name":"School of Sciences and State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Meng","family":"Zhang","sequence":"additional","affiliation":[{"name":"College of Bioscience and Biotechnology Hunan Agricultural University  Changsha China"},{"name":"School of Sciences and State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ming","family":"Li","sequence":"additional","affiliation":[{"name":"School of Sciences and State Key Laboratory of Natural Medicines China Pharmaceutical University  Nanjing 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