{
    "abstract": "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.",
    "authors": [
        {
            "affiliation": "Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.",
            "firstname": "Lars",
            "initials": "L",
            "lastname": "Binkle-Ladisch"
        },
        {
            "affiliation": "Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg O/N1, Herestraat 49-Bus 802, 3000 Leuven, Belgium.",
            "firstname": "Andy",
            "initials": "A",
            "lastname": "Pironet"
        },
        {
            "affiliation": "Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, Germany.",
            "firstname": "Andrea",
            "initials": "A",
            "lastname": "Zaliani"
        },
        {
            "affiliation": "Department of Chemistry, Evotec SE, 195 Route D'Espagne, 31036 Toulouse, France.",
            "firstname": "Chantal",
            "initials": "C",
            "lastname": "Alcouffe"
        },
        {
            "affiliation": "Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.",
            "firstname": "Daniel",
            "initials": "D",
            "lastname": "Mensching"
        },
        {
            "affiliation": "Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, Germany.",
            "firstname": "Undine",
            "initials": "U",
            "lastname": "Haferkamp"
        },
        {
            "affiliation": "Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.",
            "firstname": "Anne",
            "initials": "A",
            "lastname": "Willing"
        },
        {
            "affiliation": "Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.",
            "firstname": "Marcel S",
            "initials": "MS",
            "lastname": "Woo"
        },
        {
            "affiliation": "Department of Chemistry, Evotec SE, 195 Route D'Espagne, 31036 Toulouse, France.",
            "firstname": "Alexandre",
            "initials": "A",
            "lastname": "Erdmann"
        },
        {
            "affiliation": "SCIENAMICS GmbH, 24975 Husby, Germany.",
            "firstname": "Timm",
            "initials": "T",
            "lastname": "Jessen"
        },
        {
            "affiliation": "Evotec Asia Pte Ltd, 79 Science Park Drive, #04-05 Cintech IV, Singapore 118264, Singapore.",
            "firstname": "Stephen D",
            "initials": "SD",
            "lastname": "Hess"
        },
        {
            "affiliation": "Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, Germany.",
            "firstname": "Philip",
            "initials": "P",
            "lastname": "Gribbon"
        },
        {
            "affiliation": "Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, 22525 Hamburg, Germany.",
            "firstname": "Ole",
            "initials": "O",
            "lastname": "Pless"
        },
        {
            "affiliation": "Laboratory of Ion Channel Research, Department of Cellular and Molecular Medicine, Katholieke Universiteit Leuven, Campus Gasthuisberg O/N1, Herestraat 49-Bus 802, 3000 Leuven, Belgium.",
            "firstname": "Rudi",
            "initials": "R",
            "lastname": "Vennekens"
        },
        {
            "affiliation": "Institute of Neuroimmunology and Multiple Sclerosis, University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.",
            "firstname": "Manuel A",
            "initials": "MA",
            "lastname": "Friese"
        }
    ],
    "conclusions": null,
    "copyrights": "\u00a9 2024 The Author(s).",
    "doi": "10.1016/j.isci.2024.111425\n10.1007/s10158-018-0221-7\n10.1038/nrm1155\n10.1038/nrn725\n10.1126/science.7901908\n10.1038/s41580-023-00689-6\n10.1016/j.neulet.2017.08.048\n10.1016/S0143-4160(03)00141-6\n10.1038/nn835\n10.1523/JNEUROSCI.12-05-01882.1992\n10.3390/cells8020184\n10.1046/j.1471-4159.2001.00075.x\n10.1111/j.1471-4159.2007.04487.x\n10.1074/jbc.M600504200\n10.1172/JCI126381\n10.2174/1381612826666200113162641\n10.1177/0269881118754680\n10.1016/j.neuron.2018.12.023\n10.1016/S0140-6736(00)02326-6\n10.1038/nrd1958\n10.1002/phar.2707\n10.1016/j.coph.2005.12.002\n10.1038/s41386-023-01614-3\n10.1038/s41589-019-0449-5\n10.1126/science.aay3302\n10.1126/science.1072873\n10.1084/jem.20201290\n10.1007/978-981-10-7757-9\n10.1016/j.ceca.2019.102111\n10.1111/apha.12949\n10.1126/science.aar4510\n10.1074/jbc.M305127200\n10.1016/j.bpc.2015.06.004\n10.1038/nature24997\n10.1002/glia.23231\n10.1126/scisignal.add6364\n10.1093/cvr/cvr135\n10.1038/s41598-022-09875-6\n10.1016/j.neulet.2019.134729\n10.1038/nm.3015\n10.1007/s00424-019-02326-8\n10.1007/s00424-013-1347-4\n10.1038/nm.1899\n10.3171/2009.11.JNS081052\n10.1016/j.jid.2018.10.044\n10.1093/eurheartj/ehac354\n10.7554/eLife.66582\n10.1007/s00395-015-0501-x\n10.1172/JCI38292\n10.1172/JCI41348\n10.1371/journal.pone.0121703\n10.1038/ni.1648\n10.1126/science.1098845\n10.1016/j.ceca.2008.10.005\n10.1038/ni1441\n10.1016/j.cardiores.2006.11.023\n10.1074/jbc.M112.428219\n10.1111/bph.14220\n10.2174/138620709787047948\n10.1016/j.pharmthera.2013.01.012\n10.1038/nrd3845\n10.1126/science.aav9334\n10.1038/s41467-023-38162-9\n10.1038/nchembio.1835\n10.1038/s41467-021-22507-3\n10.1038/s41594-017-0009-1\n10.1016/j.neuron.2020.10.014\n10.1038/s41594-021-00607-4\n10.1073/pnas.1722038115\n10.1016/j.ceca.2004.11.001\n10.3389/fphar.2021.712354\n10.1016/j.lanepe.2022.100472\n10.1016/j.vhri.2023.09.008\n10.1002/agm2.12243\n10.3390/ijms20236004\n10.1016/j.ceca.2017.06.008\n10.1016/j.jala.2006.02.006\n10.1007/s12975-018-0621-3\n10.1038/s41467-023-39346-z\n10.1038/nature12823\n10.1186/1758-2946-3-33\n10.1093/bioinformatics/btn307\n10.1002/pst.449\n10.1021/ci200454v\n10.1021/acs.jcim.0c01095\n10.1093/nar/gkac305",
    "journal": "iScience",
    "keywords": [
        "Molecular biology",
        "Molecular neuroscience",
        "Neuroscience"
    ],
    "methods": null,
    "publication_date": "2024-12-17",
    "pubmed_id": "39687019\n30488358\n12838335\n11836517\n7901908\n38110635\n28843346\n12909079\n11953750\n1349638\n30791579\n11158256\n17403030\n16720574\n31661467\n31931694\n29444621\n30686733\n10859040\n16424917\n35665948\n16359918\n37369776\n31959964\n33033186\n12399596\n33661276\n31812825\n28834354\n29217581\n12799367\n26071843\n29211714\n28906027\n37279286\n21565835\n35397639\n31899311\n23160238\n31664513\n24043570\n19169264\n20035575\n30528822\n35822895\n34190686\n26043922\n19726882\n20679729\n25836769\n18758465\n15550671\n19046767\n17293867\n17188667\n23255597\n29579323\n19149494\n23356979\n23197038\n30733385\n37117175\n26053297\n33846324\n29323279\n33152265\n34168372\n29463718\n15670874\n34335274\n35910037\n37972428\n36911087\n31795242\n28728834\n29569041\n37353478\n24305161\n21982300\n18596077\n22148551\n33258376\n35489057",
    "results": null,
    "title": "Identification and development of TRPM4 antagonists to counteract neuronal excitotoxicity.",
    "xml": "<Element 'PubmedArticle' at 0x788505658ea0>"
}