Pharmacology of JNJ-28583113: A novel TRPM2 antagonist
| Autor: | Nicholas I. Carruthers, Lawrence Fourgeaud, Ning Qin, Sunil Sahdeo, Curt A. Dvorak, Anindya Bhattacharya, Brian Lord, Qi Wang, Natalie Taylor, Alan D. Wickenden, Reinhold Penner, Coate Heather R, John Starkus, Yingbo He, Timothy W. Lovenberg, Malika Faouzi |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male medicine.medical_treatment TRPM Cation Channels Pharmacology medicine.disease_cause 03 medical and health sciences Transient receptor potential channel Mice 0302 clinical medicine In vivo Drug Discovery medicine Animals Humans TRPM2 Microglia Chemistry Antagonist Rats 030104 developmental biology medicine.anatomical_structure Cytokine HEK293 Cells Pyrazoles 030217 neurology & neurosurgery Intracellular Oxidative stress HeLa Cells |
| Zdroj: | European journal of pharmacology. 853 |
| ISSN: | 1879-0712 |
| Popis: | Transient receptor potential melastatin type 2 (TRPM2) is a cation channel activated by free intracellular ADP-ribose and reactive oxygen species. TRPM2 signaling has been linked to the pathophysiology of CNS disorders such as neuropathic pain, bipolar disorder and Alzheimer's disease. In this manuscript, we describe the discovery of JNJ-28583113, a potent brain penetrant TRPM2 antagonist. Ca2+ flux assays in cells overexpressing TRPM2 and electrophysiological recordings were used to test the pharmacology of JNJ-28583113. JNJ-28583113 was assayed in vitro on GSK-3 phosphorylation levels, cell death, cytokine release in microglia and unbiased morphological phenotypic analysis. Finally, we dosed animals to evaluate its pharmacokinetic properties. Our results showed that JNJ-28583113 is a potent (126 ± 0.5 nM) TRPM2 antagonist. Blocking TRPM2 caused phosphorylation of GSK3α and β subunits. JNJ-28583113 also protected cells from oxidative stress induced cell death as well as morphological changes induced by non-cytotoxic concentrations of H2O2. In addition, inhibiting TRPM2 blunted cytokine release in response to pro-inflammatory stimuli in microglia. Lastly, we showed that JNJ-28583113 was brain penetrant but not suitable for systemic dosing as it was rapidly metabolized in vivo. While the in-vitro pharmacology of JNJ-28583113 is the best in class, its in-vivo properties would need optimization to assist in further probing key roles of TRPM2 in CNS pathophysiology. |
| Databáze: | OpenAIRE |
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