{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:37:27Z","timestamp":1793043447370,"version":"4.5.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"10","license":[{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T00:00:00Z","timestamp":1783728000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"The University of Sydney","id":[{"id":"https:\/\/ror.org\/0384j8v12","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Med Chem Res"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Interest in the P2Y6 receptor (P2Y6R) has increased substantially over the past decade, driven by evidence that pharmacological inhibition is beneficial in neurodegenerative disease models, inflammatory pathologies, and cancer. However, therapeutic targeting of the P2Y6R has remained a challenge due to a lack of available drug-like molecules. In 2023 and 2024, benzimidazole and quinoline chemotypes respectively, were reported as potent P2Y6R antagonists with pharmacological relevance in an inflammatory bowel disease model. In the present study positive and negative controls from each chemotype were selected, and their functional activity at hP2Y6R was assessed prior to chemical diversification. Contrary to the published literature, none of the antagonists exhibited functional activity in our Ca\n                    <jats:sup>2+<\/jats:sup>\n                    mobilisation assay reported herein. These findings emphasise the ongoing challenges in reliably assessing pharmacological activity at the hP2Y6R and highlight a key barrier to progression of the field.\n                  <\/jats:p>","DOI":"10.1007\/s00044-026-03591-w","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T05:07:53Z","timestamp":1783746473000},"page":"2055-2072","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Investigation of reported small molecule P2Y6 receptor antagonists"],"prefix":"10.1007","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-3730-9453","authenticated-orcid":false,"given":"Chianna","family":"Dane","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8012-4745","authenticated-orcid":false,"given":"Andr\u00e9 D.J.","family":"McKenzie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1819-3619","authenticated-orcid":false,"given":"Andrew P.","family":"Montgomery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7750-4413","authenticated-orcid":false,"given":"Jonathan","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6224-1286","authenticated-orcid":false,"given":"Eryn L.","family":"Werry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6655-0529","authenticated-orcid":false,"given":"Michael","family":"Kassiou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,11]]},"reference":[{"key":"3591_CR1","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1186\/s40035-024-00438-5","volume":"13","author":"JM Dundee","year":"2024","unstructured":"Dundee JM, Brown GC. The microglial P2Y6 receptor as a therapeutic target for neurodegenerative diseases. Translational Neurodegeneration. 2024;13:47. https:\/\/doi.org\/10.1186\/s40035-024-00438-5.","journal-title":"Translational Neurodegeneration"},{"key":"3591_CR2","doi-asserted-by":"publisher","first-page":"2209","DOI":"10.2174\/0929867329666220614100218","volume":"30","author":"Y Wang","year":"2023","unstructured":"Wang Y, Pei Y, Yao Y, et al. P2Y6R: A Promising New Target in Inflammatory Diseases and Advances in its Antagonists. Curr Med Chem. 2023;30:2209\u201324. https:\/\/doi.org\/10.2174\/0929867329666220614100218.","journal-title":"Curr Med Chem"},{"key":"3591_CR3","doi-asserted-by":"publisher","first-page":"110148","DOI":"10.1016\/j.celrep.2021.110148","volume":"37","author":"M Puigdell\u00edvol","year":"2021","unstructured":"Puigdell\u00edvol M, Milde S, Vilalta A, et al. The microglial P2Y6 receptor mediates neuronal loss and memory deficits in neurodegeneration. Cell Rep. 2021;37:110148. https:\/\/doi.org\/10.1016\/j.celrep.2021.110148.","journal-title":"Cell Rep"},{"key":"3591_CR4","doi-asserted-by":"publisher","first-page":"1595","DOI":"10.3390\/cells9071595","volume":"9","author":"S Anwar","year":"2020","unstructured":"Anwar S, Pons V, Rivest S, Microglia Purinoceptor. P2Y6: An Emerging Therapeutic Target in CNS Diseases. Cells. 2020;9:1595. https:\/\/doi.org\/10.3390\/cells9071595.","journal-title":"Cells"},{"key":"3591_CR5","doi-asserted-by":"publisher","first-page":"1091","DOI":"10.1038\/nature05704","volume":"446","author":"S Koizumi","year":"2007","unstructured":"Koizumi S, Shigemoto-Mogami Y, Nasu-Tada K, et al. UDP acting at P2Y6 receptors is a mediator of microglial phagocytosis. Nature. 2007;446:1091\u20135. https:\/\/doi.org\/10.1038\/nature05704.","journal-title":"Nature"},{"key":"3591_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15257770.2025.2584080","volume":"0","author":"K Ghimeray","year":"2025","unstructured":"Ghimeray K, Sharma S, Rahman MM, et al. P2Y6 receptor inhibition arrests tumor cell progression in a mouse lymphoma model. Nucleosides Nucleotides Nucleic Acids. 2025;0:1\u201319. https:\/\/doi.org\/10.1080\/15257770.2025.2584080.","journal-title":"Nucleosides Nucleotides Nucleic Acids"},{"key":"3591_CR7","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1002\/glia.22693","volume":"62","author":"JJ Neher","year":"2014","unstructured":"Neher JJ, Neniskyte U, Hornik T, et al. Inhibition of UDP\/P2Y6 purinergic signaling prevents phagocytosis of viable neurons by activated microglia in vitro and in vivo. Glia. 2014;62:1463\u201375. https:\/\/doi.org\/10.1002\/glia.22693.","journal-title":"Glia"},{"key":"3591_CR8","doi-asserted-by":"publisher","first-page":"4139","DOI":"10.1007\/s12035-024-04531-8","volume":"62","author":"Y Zhang","year":"2025","unstructured":"Zhang Y, Tang Y, Illes P. Modification of Neural Circuit Functions by Microglial P2Y6 Receptors in Health and Neurodegeneration. Mol Neurobiol. 2025;62:4139\u201348. https:\/\/doi.org\/10.1007\/s12035-024-04531-8.","journal-title":"Mol Neurobiol"},{"key":"3591_CR9","doi-asserted-by":"publisher","first-page":"177513","DOI":"10.1016\/j.ejphar.2025.177513","volume":"998","author":"L Li","year":"2025","unstructured":"Li L, Lai L, Qiu D, et al. P2Y6 receptor: A promising therapeutic target for atherosclerosis. Eur J Pharmacol. 2025;998:177513. https:\/\/doi.org\/10.1016\/j.ejphar.2025.177513.","journal-title":"Eur J Pharmacol"},{"key":"3591_CR10","doi-asserted-by":"publisher","first-page":"9057","DOI":"10.1021\/acs.jmedchem.5c00249","volume":"68","author":"M Puthanveedu","year":"2025","unstructured":"Puthanveedu M, Knight R, Stocks MJ. Drug-like Antagonists of P2Y Receptor Subtypes: An Update. J Med Chem. 2025;68:9057\u201383. https:\/\/doi.org\/10.1021\/acs.jmedchem.5c00249.","journal-title":"J Med Chem"},{"key":"3591_CR11","doi-asserted-by":"publisher","first-page":"1763","DOI":"10.1016\/j.bcp.2004.01.011","volume":"67","author":"LK Mamedova","year":"2004","unstructured":"Mamedova LK, Joshi BV, Gao Z-G, et al. Diisothiocyanate derivatives as potent, insurmountable antagonists of P2Y6 nucleotide receptors. Biochem Pharmacol. 2004;67:1763\u201370. https:\/\/doi.org\/10.1016\/j.bcp.2004.01.011.","journal-title":"Biochem Pharmacol"},{"key":"3591_CR12","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.3389\/fimmu.2017.01028","volume":"8","author":"T M\u00fcller","year":"2017","unstructured":"M\u00fcller T, Fay S, Vieira RP, et al. P2Y6 Receptor Activation Promotes Inflammation and Tissue Remodeling in Pulmonary Fibrosis. Front Immunol. 2017;8:1028. https:\/\/doi.org\/10.3389\/fimmu.2017.01028.","journal-title":"Front Immunol"},{"key":"3591_CR13","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1016\/j.jocn.2018.07.013","volume":"56","author":"D Huang","year":"2018","unstructured":"Huang D, Yang J, Liu X, et al. P2Y6 receptor activation is involved in the development of neuropathic pain induced by chronic constriction injury of the sciatic nerve in rats. J Clin Neurosci. 2018;56:156\u201362. https:\/\/doi.org\/10.1016\/j.jocn.2018.07.013.","journal-title":"J Clin Neurosci"},{"key":"3591_CR14","doi-asserted-by":"publisher","first-page":"476","DOI":"10.3389\/fncel.2019.00476","volume":"13","author":"\u00c1 Oliveira-Giacomelli","year":"2019","unstructured":"Oliveira-Giacomelli \u00c1, Albino M, de Souza C. P2Y6 and P2X7 Receptor Antagonism Exerts Neuroprotective\/ Neuroregenerative Effects in an Animal Model of Parkinson\u2019s Disease. Front Cell Neurosci. 2019;13:476. https:\/\/doi.org\/10.3389\/fncel.2019.00476.","journal-title":"Front Cell Neurosci"},{"key":"3591_CR15","doi-asserted-by":"publisher","first-page":"416","DOI":"10.1111\/cns.13296","volume":"26","author":"R-X Wen","year":"2020","unstructured":"Wen R-X, Shen H, Huang S-X, et al. P2Y6 receptor inhibition aggravates ischemic brain injury by reducing microglial phagocytosis. CNS Neurosci Ther. 2020;26:416\u201329. https:\/\/doi.org\/10.1111\/cns.13296.","journal-title":"CNS Neurosci Ther"},{"key":"3591_CR16","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1007\/s11302-021-09813-7","volume":"17","author":"CE M\u00fcller","year":"2021","unstructured":"M\u00fcller CE, Namasivayam V. Recommended tool compounds and drugs for blocking P2X and P2Y receptors. Purinergic Signalling. 2021;17:633\u201348. https:\/\/doi.org\/10.1007\/s11302-021-09813-7.","journal-title":"Purinergic Signalling"},{"key":"3591_CR17","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1111\/j.1476-5381.2009.00497.x","volume":"159","author":"P-J Guns","year":"2010","unstructured":"Guns P-J, Hendrickx J, Assche T, et al. P2Y receptors and atherosclerosis in apolipoprotein E-deficient mice - Guns\u2009\u2013\u20092010 -. Br J Pharmacol - Wiley Online Libr. 2010;159:326\u201336. https:\/\/doi.org\/10.1111\/j.1476-5381.2009.00497.x.","journal-title":"Br J Pharmacol - Wiley Online Libr"},{"key":"3591_CR18","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1007\/s11302-008-9106-2","volume":"5","author":"KA Jacobson","year":"2009","unstructured":"Jacobson KA, Ivanov AA, de Castro S, et al. Development of selective agonists and antagonists of P2Y receptors. Purinergic Signalling. 2009;5:75\u201389. https:\/\/doi.org\/10.1007\/s11302-008-9106-2.","journal-title":"Purinergic Signalling"},{"key":"3591_CR19","doi-asserted-by":"publisher","first-page":"137","DOI":"10.1016\/j.lfs.2017.05.017","volume":"180","author":"M Ito","year":"2017","unstructured":"Ito M, Egashira S, Yoshida K, et al. Identification of novel selective P2Y6 receptor antagonists by high-throughput screening assay. Life Sci. 2017;180:137\u201342. https:\/\/doi.org\/10.1016\/j.lfs.2017.05.017.","journal-title":"Life Sci"},{"key":"3591_CR20","doi-asserted-by":"publisher","first-page":"128008","DOI":"10.1016\/j.bmcl.2021.128008","volume":"41","author":"Y-H Jung","year":"2021","unstructured":"Jung Y-H, Jain S, Gopinatth V, et al. Structure activity relationship of 3-nitro-2-(trifluoromethyl)-2H-chromene derivatives as P2Y6 receptor antagonists. Bioorg Med Chem Lett. 2021;41:128008. https:\/\/doi.org\/10.1016\/j.bmcl.2021.128008.","journal-title":"Bioorg Med Chem Lett"},{"key":"3591_CR21","doi-asserted-by":"publisher","first-page":"128981","DOI":"10.1016\/j.bmcl.2022.128981","volume":"75","author":"Y-H Jung","year":"2022","unstructured":"Jung Y-H, Shah Q, Lewicki SA, et al. Synthesis and pharmacological characterization of multiply substituted 2H-chromene derivatives as P2Y6 receptor antagonists. Bioorg Med Chem Lett. 2022;75:128981. https:\/\/doi.org\/10.1016\/j.bmcl.2022.128981.","journal-title":"Bioorg Med Chem Lett"},{"key":"3591_CR22","doi-asserted-by":"publisher","first-page":"1366","DOI":"10.3390\/cells13161366","volume":"13","author":"P Oliva","year":"2024","unstructured":"Oliva P, Pramanik A, Jung Y-H, et al. Functionalized Congeners of 2H-Chromene P2Y6 Receptor Antagonists. Cells. 2024;13:1366. https:\/\/doi.org\/10.3390\/cells13161366.","journal-title":"Cells"},{"key":"3591_CR23","doi-asserted-by":"publisher","first-page":"6315","DOI":"10.1021\/acs.jmedchem.3c00210","volume":"66","author":"Y Zhu","year":"2023","unstructured":"Zhu Y, Zhou M, Cheng X, et al. Discovery of Selective P2Y6R Antagonists with High Affinity and In Vivo Efficacy for Inflammatory Disease Therapy. J Med Chem. 2023;66:6315\u201332. https:\/\/doi.org\/10.1021\/acs.jmedchem.3c00210.","journal-title":"J Med Chem"},{"key":"3591_CR24","doi-asserted-by":"publisher","first-page":"116890","DOI":"10.1016\/j.ejmech.2024.116890","volume":"279","author":"Y Zhao","year":"2024","unstructured":"Zhao Y, Han B, Wei Z, et al. Discovery of a potent, Highly selective, and In vivo anti-inflammatory Efficacious, P2Y6R antagonist with a novel quinoline-pyrazole scaffold. Eur J Med Chem. 2024;279:116890. https:\/\/doi.org\/10.1016\/j.ejmech.2024.116890.","journal-title":"Eur J Med Chem"},{"key":"3591_CR25","unstructured":"Li H, Qinghua H, Zhu Y, et al. 2-pyrazole-3-benzimidazole derivative as well as preparation method and application thereof. CN114276338; 2022."},{"key":"3591_CR26","unstructured":"Hu Q, Li H, Leng H, et al. Benzoxazole compound as well as preparation method, pharmaceutical composition and application thereof. CN114478511; 2022."},{"key":"3591_CR27","doi-asserted-by":"publisher","first-page":"eabj0644","DOI":"10.1126\/scisignal.abj0644","volume":"15","author":"K Nishiyama","year":"2022","unstructured":"Nishiyama K, Nishimura A, Shimoda K, et al. Redox-dependent internalization of the purinergic P2Y6 receptor limits colitis progression. Sci Signal. 2022;15:eabj0644. https:\/\/doi.org\/10.1126\/scisignal.abj0644.","journal-title":"Sci Signal"},{"key":"3591_CR28","doi-asserted-by":"publisher","unstructured":"Oyedele A-QK, Ogunlana AT, Boyenle ID et al. Docking covalent targets for drug discovery: stimulating the computer-aided drug design community of possible pitfalls and erroneous practices. Mol Diversity. 2022:1\u201325. https:\/\/doi.org\/10.1007\/s11030-022-10523-4","DOI":"10.1007\/s11030-022-10523-4"},{"key":"3591_CR29","doi-asserted-by":"publisher","first-page":"8108","DOI":"10.1021\/jm050911p","volume":"48","author":"S Costanzi","year":"2005","unstructured":"Costanzi S, Joshi BV, Maddileti S, et al. Human P2Y6 Receptor: Molecular Modeling Leads to the Rational Design of a Novel Agonist Based on a Unique Conformational Preference. J Med Chem. 2005;48:8108\u201311. https:\/\/doi.org\/10.1021\/jm050911p.","journal-title":"J Med Chem"},{"key":"3591_CR30","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1007\/978-1-61779-588-6_11","volume":"857","author":"S Costanzi","year":"2012","unstructured":"Costanzi S, Clifton. N j). 2012;857:259\u201379. https:\/\/doi.org\/10.1007\/978-1-61779-588-6_11.","journal-title":"N j)"},{"key":"3591_CR31","doi-asserted-by":"publisher","first-page":"815","DOI":"10.1002\/wmts.68","volume":"1","author":"KA Jacobson","year":"2012","unstructured":"Jacobson KA, Jayasekara MPS, Costanzi S. Molecular structure of P2Y receptors: mutagenesis, modeling, and chemical probes. Wiley Interdisciplinary Reviews: Membrane Transp Signal. 2012;1:815\u201327. https:\/\/doi.org\/10.1002\/wmts.68.","journal-title":"Wiley Interdisciplinary Reviews: Membrane Transp Signal"},{"key":"3591_CR32","doi-asserted-by":"publisher","unstructured":"Alberto AVP, Santos LHS, Ferreira R et al. A Brief View of Molecular Modeling Approaches to P2 Receptors. Receptors P1 and P2 as Targets for Drug Therapy in Humans, IntechOpen; 2019. https:\/\/doi.org\/10.5772\/intechopen.86862","DOI":"10.5772\/intechopen.86862"},{"key":"3591_CR33","doi-asserted-by":"publisher","first-page":"1662","DOI":"10.3390\/ph16121662","volume":"16","author":"FA Binbay","year":"2023","unstructured":"Binbay FA, Rathod DC, George AAP, et al. Quality Assessment of Selected Protein Structures Derived from Homology Modeling and AlphaFold. Pharmaceuticals. 2023;16:1662. https:\/\/doi.org\/10.3390\/ph16121662.","journal-title":"Pharmaceuticals"},{"key":"3591_CR34","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1038\/s41586-021-03819-2","volume":"596","author":"J Jumper","year":"2021","unstructured":"Jumper J, Evans R, Pritzel A, et al. Highly accurate protein structure prediction with AlphaFold. Nature. 2021;596:583\u20139. https:\/\/doi.org\/10.1038\/s41586-021-03819-2.","journal-title":"Nature"},{"key":"3591_CR35","doi-asserted-by":"publisher","first-page":"3494","DOI":"10.1016\/j.csbj.2020.11.007","volume":"18","author":"T Hameduh","year":"2020","unstructured":"Hameduh T, Haddad Y, Adam V, et al. Homology modeling in the time of collective and artificial intelligence. Comput Struct Biotechnol J. 2020;18:3494\u2013506. https:\/\/doi.org\/10.1016\/j.csbj.2020.11.007.","journal-title":"Comput Struct Biotechnol J"},{"key":"3591_CR36","doi-asserted-by":"publisher","first-page":"e1464","DOI":"10.1002\/wcms.1464","volume":"10","author":"A Neumann","year":"2020","unstructured":"Neumann A, M\u00fcller CE, Namasivayam V. P2Y1-like nucleotide receptors\u2014Structures, molecular modeling, mutagenesis, and oligomerization. WIREs Comput Mol Sci. 2020;10:e1464. https:\/\/doi.org\/10.1002\/wcms.1464.","journal-title":"WIREs Comput Mol Sci"},{"key":"3591_CR37","doi-asserted-by":"publisher","first-page":"217","DOI":"10.2174\/138920306777452312","volume":"7","author":"Z Xiang","year":"2006","unstructured":"Xiang Z. Advances in Homology Protein Structure Modeling. Curr Protein Pept Sci. 2006;7:217\u201327. https:\/\/doi.org\/10.2174\/138920306777452312.","journal-title":"Curr Protein Pept Sci"},{"key":"3591_CR38","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1038\/nature14287","volume":"520","author":"D Zhang","year":"2015","unstructured":"Zhang D, Gao Z-G, Zhang K, et al. Two disparate ligand binding sites in the human P2Y1 receptor. Nature. 2015;520:317\u201321. https:\/\/doi.org\/10.1038\/nature14287.","journal-title":"Nature"},{"key":"3591_CR39","doi-asserted-by":"publisher","unstructured":"Ram\u00edrez D, Caballero J. Is It Reliable to Use Common Molecular Docking Methods for Comparing the Binding Affinities of Enantiomer Pairs for Their Protein Target? Int J Mol Sci. 2016;17. https:\/\/doi.org\/10.3390\/ijms17040525.","DOI":"10.3390\/ijms17040525"},{"key":"3591_CR40","doi-asserted-by":"publisher","first-page":"231","DOI":"10.1016\/S0014-2999(97)89184-4","volume":"329","author":"B Robaye","year":"1997","unstructured":"Robaye B, Boeynaems J-M, Communi D. Slow desensitization of the human P2Y6 receptor. Eur J Pharmacol. 1997;329:231\u20136. https:\/\/doi.org\/10.1016\/S0014-2999(97)89184-4.","journal-title":"Eur J Pharmacol"},{"key":"3591_CR41","doi-asserted-by":"publisher","first-page":"1341","DOI":"10.1124\/mol.109.058578","volume":"76","author":"RL Carter","year":"2009","unstructured":"Carter RL, Fricks IP, Barrett MO, et al. Quantification of Gi-Mediated Inhibition of Adenylyl Cyclase Activity Reveals That UDP Is a Potent Agonist of the Human P2Y14 Receptor. Mol Pharmacol. 2009;76:1341\u20138. https:\/\/doi.org\/10.1124\/mol.109.058578.","journal-title":"Mol Pharmacol"},{"key":"3591_CR42","doi-asserted-by":"publisher","unstructured":"Woszczek G, Chen L-Y, Alsaaty S et al. Concentration dependent non-CysLT1 receptor mediated inhibitory activity of leukotriene receptor antagonists. Journal of Immunology (Baltimore, Md : 1950). 2010;184:2219\u201325. https:\/\/doi.org\/10.4049\/jimmunol.0900071","DOI":"10.4049\/jimmunol.0900071"},{"key":"3591_CR43","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1038\/sj.bjp.0704566","volume":"135","author":"TD Werry","year":"2002","unstructured":"Werry TD, Christie MI, Dainty IA, et al. Ca2\u2009+\u2009signalling by recombinant human CXCR2 chemokine receptors is potentiated by P2Y nucleotide receptors in HEK cells. Br J Pharmacol. 2002;135:1199\u2013208. https:\/\/doi.org\/10.1038\/sj.bjp.0704566.","journal-title":"Br J Pharmacol"},{"key":"3591_CR44","doi-asserted-by":"publisher","first-page":"1093","DOI":"10.1161\/01.HYP.36.6.1093","volume":"36","author":"L van der Weyden","year":"2000","unstructured":"van der Weyden L, Adams DJ, Morris BJ. Capacity for Purinergic Control of Renin Promoter via P2Y11 Receptor and cAMP Pathways. Hypertension. 2000;36:1093\u20138. https:\/\/doi.org\/10.1161\/01.HYP.36.6.1093.","journal-title":"Hypertension"},{"key":"3591_CR45","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1111\/j.1476-5381.1993.tb13960.x","volume":"110","author":"PA Iredale","year":"1993","unstructured":"Iredale PA, Hill SJ. Increases in intracellular calcium via activation of an endogenous P2-purinoceptor in cultured CHO-K1 cells. Br J Pharmacol. 1993;110:1305\u201310. https:\/\/doi.org\/10.1111\/j.1476-5381.1993.tb13960.x.","journal-title":"Br J Pharmacol"},{"key":"3591_CR46","doi-asserted-by":"publisher","first-page":"119","DOI":"10.1038\/nature13288","volume":"509","author":"J Zhang","year":"2014","unstructured":"Zhang J, Zhang K, Gao Z-G, et al. Agonist-bound structure of the human P2Y12 receptor. Nature. 2014;509:119\u201322. https:\/\/doi.org\/10.1038\/nature13288.","journal-title":"Nature"},{"key":"3591_CR47","doi-asserted-by":"publisher","first-page":"220","DOI":"10.1124\/mol.114.095711","volume":"88","author":"KA Jacobson","year":"2015","unstructured":"Jacobson KA, Paoletta S, Katritch V, et al. Nucleotides Acting at P2Y Receptors: Connecting Structure and Function. Mol Pharmacol. 2015;88:220\u201330. https:\/\/doi.org\/10.1124\/mol.114.095711.","journal-title":"Mol Pharmacol"},{"key":"3591_CR48","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1016\/S0014-2999(99)00350-7","volume":"376","author":"BR Bianchi","year":"1999","unstructured":"Bianchi BR, Lynch KJ, Touma E, et al. Pharmacological characterization of recombinant human and rat P2X receptor subtypes. Eur J Pharmacol. 1999;376:127\u201338. https:\/\/doi.org\/10.1016\/S0014-2999(99)00350-7.","journal-title":"Eur J Pharmacol"},{"key":"3591_CR49","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1111\/j.1476-5381.1996.tb15381.x","volume":"118","author":"JB Schachter","year":"1996","unstructured":"Schachter JB, Li Q, Boyer JL, et al. Second messenger cascade specificity and pharmacological selectivity of the human P2Y1-purinoceptor. Br J Pharmacol. 1996;118:167\u201373. https:\/\/doi.org\/10.1111\/j.1476-5381.1996.tb15381.x.","journal-title":"Br J Pharmacol"},{"key":"3591_CR50","doi-asserted-by":"publisher","first-page":"1250","DOI":"10.1111\/j.1476-5381.2010.00863.x","volume":"161","author":"SJ Charlton","year":"2010","unstructured":"Charlton SJ, Vauquelin G. Elusive equilibrium: the challenge of interpreting receptor pharmacology using calcium assays. Br J Pharmacol. 2010;161:1250\u201365. https:\/\/doi.org\/10.1111\/j.1476-5381.2010.00863.x.","journal-title":"Br J Pharmacol"},{"key":"3591_CR51","doi-asserted-by":"publisher","first-page":"2441","DOI":"10.1016\/j.tetlet.2017.05.029","volume":"58","author":"SM Ruatta","year":"2017","unstructured":"Ruatta SM, Murgu\u00eda MC, Ram\u00edrez de Arellano C, et al. Regio-specific synthesis of new 1-(tert-butyl)-1H-pyrazolecarboxamide derivatives. Tetrahedron Lett. 2017;58:2441\u20134. https:\/\/doi.org\/10.1016\/j.tetlet.2017.05.029.","journal-title":"Tetrahedron Lett"},{"key":"3591_CR52","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/S0022-2836(02)00470-9","volume":"320","author":"MP Jacobson","year":"2002","unstructured":"Jacobson MP, Friesner RA, Xiang Z, et al. On the Role of the Crystal Environment in Determining Protein Side-chain Conformations. J Mol Biol. 2002;320:597\u2013608. https:\/\/doi.org\/10.1016\/S0022-2836(02)00470-9.","journal-title":"J Mol Biol"},{"key":"3591_CR53","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1002\/prot.10613","volume":"55","author":"MP Jacobson","year":"2004","unstructured":"Jacobson MP, Pincus DL, Rapp CS, et al. A hierarchical approach to all-atom protein loop prediction. Proteins Struct Funct Bioinform. 2004;55:351\u201367. https:\/\/doi.org\/10.1002\/prot.10613.","journal-title":"Proteins Struct Funct Bioinform"},{"key":"3591_CR54","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1007\/s10822-007-9133-z","volume":"21","author":"JC Shelley","year":"2007","unstructured":"Shelley JC, Cholleti A, Frye LL, et al. Epik: a software program for pK(a) prediction and protonation state generation for drug-like molecules. J Comput Aided Mol Des. 2007;21:681\u201391. https:\/\/doi.org\/10.1007\/s10822-007-9133-z.","journal-title":"J Comput Aided Mol Des"},{"key":"3591_CR55","doi-asserted-by":"publisher","first-page":"4291","DOI":"10.1021\/acs.jctc.1c00302","volume":"17","author":"C Lu","year":"2021","unstructured":"Lu C, Wu C, Ghoreishi D, et al. OPLS4: Improving Force Field Accuracy on Challenging Regimes of Chemical Space. J Chem Theory Comput. 2021;17:4291\u2013300. https:\/\/doi.org\/10.1021\/acs.jctc.1c00302.","journal-title":"J Chem Theory Comput"},{"key":"3591_CR56","doi-asserted-by":"publisher","first-page":"6177","DOI":"10.1021\/jm051256o","volume":"49","author":"RA Friesner","year":"2006","unstructured":"Friesner RA, Murphy RB, Repasky MP, et al. Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein\u2013Ligand Complexes. J Med Chem. 2006;49:6177\u201396. https:\/\/doi.org\/10.1021\/jm051256o.","journal-title":"J Med Chem"},{"key":"3591_CR57","doi-asserted-by":"publisher","first-page":"534","DOI":"10.1021\/jm050540c","volume":"49","author":"W Sherman","year":"2006","unstructured":"Sherman W, Day T, Jacobson MP, et al. Novel Procedure for Modeling Ligand\/Receptor Induced Fit Effects. J Med Chem. 2006;49:534\u201353. https:\/\/doi.org\/10.1021\/jm050540c.","journal-title":"J Med Chem"},{"key":"3591_CR58","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1021\/jm0306430","volume":"47","author":"RA Friesner","year":"2004","unstructured":"Friesner RA, Banks JL, Murphy RB, et al. Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy. J Med Chem. 2004;47:1739\u201349. https:\/\/doi.org\/10.1021\/jm0306430.","journal-title":"J Med Chem"}],"container-title":["Medicinal Chemistry Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00044-026-03591-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00044-026-03591-w","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00044-026-03591-w.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,26]],"date-time":"2026-10-26T19:02:26Z","timestamp":1793041346000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00044-026-03591-w"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,11]]},"references-count":58,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["3591"],"URL":"https:\/\/doi.org\/10.1007\/s00044-026-03591-w","relation":{},"ISSN":["1054-2523","1554-8120"],"issn-type":[{"value":"1054-2523","type":"print"},{"value":"1554-8120","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,11]]},"assertion":[{"value":"6 February 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 June 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","label":"Conflict of interest","group":{"name":"EthicsHeading","label":"Declarations"}}]}}