دورية أكاديمية
pH Dependence of a GPR4 Selective Antagonist Hampers Its Therapeutic Potential.
العنوان: | pH Dependence of a GPR4 Selective Antagonist Hampers Its Therapeutic Potential. |
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المؤلفون: | Stalewski J; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Shih AY; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Papazyan R; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Ramirez J; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Ibanez G; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Hsiao P; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Yue Y; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Yin J; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Badger C; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Wu S; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Ueki A; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Fuchs BC; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.)., Rives ML; Departments of Chemistry (J.S.); Computer-Aided Drug Discovery (A.Y.S.); Gastroenterology (R.P., B.C.F.); Molecular and Cellular Pharmacology-Target Validation and Functional Genomics (J.R., M.-L.R.); In Vivo Pharmacology (G.I.); DMPK (P.H.); Computational Biology (Y.Y., J.Y., C.B.), Ferring Research Institute Inc., San Diego, California; and Biosensing Instrument, Tempe, Arizona (S.W., A.U.) marie-laure.rives@ferring.com. |
المصدر: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 Jul; Vol. 386 (1), pp. 35-44. Date of Electronic Publication: 2023 May 04. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't |
اللغة: | English |
بيانات الدورية: | Publisher: American Society for Pharmacology and Experimental Therapeutics Country of Publication: United States NLM ID: 0376362 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1521-0103 (Electronic) Linking ISSN: 00223565 NLM ISO Abbreviation: J Pharmacol Exp Ther Subsets: MEDLINE |
أسماء مطبوعة: | Publication: 1999- : Bethesda, MD : American Society for Pharmacology and Experimental Therapeutics Original Publication: Baltimore : Williams & Wilkins |
مواضيع طبية MeSH: | Colitis*/metabolism , Inflammatory Bowel Diseases*/drug therapy, Humans ; Animals ; Mice ; Receptors, G-Protein-Coupled/metabolism ; Inflammation ; Hydrogen-Ion Concentration |
مستخلص: | Inflammatory bowel disease (IBD) is characterized by chronic mucosal inflammation of the gastrointestinal tract and is associated with extracellular acidification of mucosal tissue. Several extracellular pH-sensing receptors, including G protein-coupled receptor 4 (GPR4), play an important role in the regulation of inflammatory and immune responses, and GPR4 deficiency has been shown to be protective in IBD animal models. To confirm the therapeutic potential of GPR4 antagonism in IBD, we tested Compound 13, a selective GPR4 antagonist, in the interleukin 10-/- mouse model of colitis. Despite good exposures and albeit there was a trend toward improvement for a few readouts, Compound 13 treatment did not improve colitis in this model, and there were no signs of target engagement. Interestingly, Compound 13 behaved as an "orthosteric" antagonist, i.e., its potency was pH dependent and mostly inactive at pH levels lower than 6.8 with preferential binding to the inactive conformation of GPR4. Mutagenesis studies confirmed Compound 13 likely binds to the conserved orthosteric binding site in G protein-coupled receptors, where a histidine sits in GPR4 likely preventing Compound 13 binding when protonated in acidic conditions. While the exact mucosal pH in the human disease and relevant IBD mice models is unknown, it is well established that the degree of acidosis is positively correlated with the degree of inflammation, suggesting Compound 13 is not an ideal tool to study the role of GPR4 in moderate to severe inflammatory conditions. SIGNIFICANCE STATEMENT: Compound 13, a reported selective GPR4 antagonist, has been widely used to assess the therapeutic potential of GPR4, a pH-sensing receptor, for numerous indications. Its pH dependence and mechanism of inhibition identified in this study clearly highlights the limitations of this chemotype for target validation. (Copyright © 2023 by The Author(s).) |
المشرفين على المادة: | 0 (Receptors, G-Protein-Coupled) 0 (GPR4 protein, human) |
تواريخ الأحداث: | Date Created: 20230504 Date Completed: 20230619 Latest Revision: 20231207 |
رمز التحديث: | 20231215 |
DOI: | 10.1124/jpet.122.001554 |
PMID: | 37142444 |
قاعدة البيانات: | MEDLINE |
تدمد: | 1521-0103 |
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DOI: | 10.1124/jpet.122.001554 |