Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity
Summary: Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-12-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224026506 |
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| author | Lars Binkle-Ladisch Andy Pironet Andrea Zaliani Chantal Alcouffe Daniel Mensching Undine Haferkamp Anne Willing Marcel S. Woo Alexandre Erdmann Timm Jessen Stephen D. Hess Philip Gribbon Ole Pless Rudi Vennekens Manuel A. Friese |
| author_facet | Lars Binkle-Ladisch Andy Pironet Andrea Zaliani Chantal Alcouffe Daniel Mensching Undine Haferkamp Anne Willing Marcel S. Woo Alexandre Erdmann Timm Jessen Stephen D. Hess Philip Gribbon Ole Pless Rudi Vennekens Manuel A. Friese |
| author_sort | Lars Binkle-Ladisch |
| collection | DOAJ |
| description | Summary: Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible approach is to modulate NMDAR activity or calcium signaling indirectly. In this respect, the calcium-activated non-selective cation channel transient receptor potential melastatin 4 (TRPM4) has been identified as a promising target. However, high affinity and specific antagonists are lacking. Here, we conducted high-throughput screening of a compound library to identify high affinity TRPM4 antagonists. This yielded five lead compound series with nanomolar half-maximal inhibitory concentration values. Through medicinal chemistry optimization of two series, we established detailed structure-activity relationships and inhibition of excitotoxicity in neurons. Moreover, we identified their potential binding site supported by electrophysiological measurements. These potent TRPM4 antagonists are promising drugs for treating neurodegenerative disorders and TRPM4-related pathologies, potentially overcoming previous therapeutic challenges. |
| format | Article |
| id | doaj-art-7c4743fbba874384a913ff92e62451a3 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-7c4743fbba874384a913ff92e62451a32024-12-22T05:29:20ZengElsevieriScience2589-00422024-12-012712111425Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicityLars Binkle-Ladisch0Andy Pironet1Andrea Zaliani2Chantal Alcouffe3Daniel Mensching4Undine Haferkamp5Anne Willing6Marcel S. Woo7Alexandre Erdmann8Timm Jessen9Stephen D. Hess10Philip Gribbon11Ole Pless12Rudi Vennekens13Manuel A. Friese14Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyLaboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg O/N1, Herestraat 49-Bus 802, 3000 Leuven, BelgiumFraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, GermanyDepartment of Chemistry, Evotec SE, 195 Route D'Espagne, 31036 Toulouse, FranceInstitute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyInstitute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, GermanyDepartment of Chemistry, Evotec SE, 195 Route D'Espagne, 31036 Toulouse, FranceSCIENAMICS GmbH, 24975 Husby, GermanyEvotec Asia Pte Ltd, 79 Science Park Drive, #04-05 Cintech IV, Singapore 118264, SingaporeFraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, GermanyFraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, GermanyLaboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg O/N1, Herestraat 49-Bus 802, 3000 Leuven, BelgiumInstitute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Corresponding authorSummary: Neurodegeneration in central nervous system disorders is linked to dysregulated neuronal calcium. Direct inhibition of glutamate-induced neuronal calcium influx, particularly via N-methyl-D-aspartate receptors (NMDAR), has led to adverse effects and clinical trial failures. A more feasible approach is to modulate NMDAR activity or calcium signaling indirectly. In this respect, the calcium-activated non-selective cation channel transient receptor potential melastatin 4 (TRPM4) has been identified as a promising target. However, high affinity and specific antagonists are lacking. Here, we conducted high-throughput screening of a compound library to identify high affinity TRPM4 antagonists. This yielded five lead compound series with nanomolar half-maximal inhibitory concentration values. Through medicinal chemistry optimization of two series, we established detailed structure-activity relationships and inhibition of excitotoxicity in neurons. Moreover, we identified their potential binding site supported by electrophysiological measurements. These potent TRPM4 antagonists are promising drugs for treating neurodegenerative disorders and TRPM4-related pathologies, potentially overcoming previous therapeutic challenges.http://www.sciencedirect.com/science/article/pii/S2589004224026506Molecular biologyNeuroscienceMolecular neuroscience |
| spellingShingle | Lars Binkle-Ladisch Andy Pironet Andrea Zaliani Chantal Alcouffe Daniel Mensching Undine Haferkamp Anne Willing Marcel S. Woo Alexandre Erdmann Timm Jessen Stephen D. Hess Philip Gribbon Ole Pless Rudi Vennekens Manuel A. Friese Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity iScience Molecular biology Neuroscience Molecular neuroscience |
| title | Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity |
| title_full | Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity |
| title_fullStr | Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity |
| title_full_unstemmed | Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity |
| title_short | Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity |
| title_sort | identification and development of trpm4 antagonists to counteract neuronal excitotoxicity |
| topic | Molecular biology Neuroscience Molecular neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224026506 |
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