Novel selective, potent naphthyl TRPM8 antagonists identified through a combined ligand- and structure-based virtual screening approach
| Autor: | Alessandro Taddei, Lorena Za, Giulio Vistoli, Marica Gemei, Andrea Rossignoli, Cinzia Nucci, Andrea R. Beccari, Nazareno Menegatti, Chiara Liberati, Matteo Lo Monte, Silvia Bovolenta, Laura Brandolini, Marco Fanton, Alessandro Pedretti, Angela Molteni |
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| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Molecular Conformation Quantitative Structure-Activity Relationship TRPM Cation Channels lcsh:Medicine Molecular Dynamics Simulation Pharmacology Ligands Article Cell Line 03 medical and health sciences Transient receptor potential channel chemistry.chemical_compound In vivo Drug Discovery medicine TRPM8 Animals Humans lcsh:Science Virtual screening Multidisciplinary Dose-Response Relationship Drug Molecular Structure Urinary Bladder Overactive lcsh:R Icilin Publisher Correction High-Throughput Screening Assays Rats 3. Good health Molecular Docking Simulation 030104 developmental biology Allodynia chemistry Competitive antagonist Mutation Hyperalgesia lcsh:Q medicine.symptom |
| Zdroj: | Scientific Reports, Vol 7, Iss 1, Pp 1-15 (2017) Scientific Reports |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-017-11194-0 |
| Popis: | Transient receptor potential melastatin 8 (TRPM8), a nonselective cation channel, is the predominant mammalian cold temperature thermosensor and it is activated by cold temperatures and cooling compounds, such as menthol and icilin. Because of its role in cold allodynia, cold hyperalgesia and painful syndromes TRPM8 antagonists are currently being pursued as potential therapeutic agents for the treatment of pain hypersensitivity. Recently TRPM8 has been found in subsets of bladder sensory nerve fibres, providing an opportunity to understand and treat chronic hypersensitivity. However, most of the known TRPM8 inhibitors lack selectivity, and only three selective compounds have reached clinical trials to date. Here, we applied two virtual screening strategies to find new, clinics suitable, TRPM8 inhibitors. This strategy enabled us to identify naphthyl derivatives as a novel class of potent and selective TRPM8 inhibitors. Further characterization of the pharmacologic properties of the most potent compound identified, compound 1, confirmed that it is a selective, competitive antagonist inhibitor of TRPM8. Compound 1 also proved itself active in a overreactive bladder model in vivo. Thus, the novel naphthyl derivative compound identified here could be optimized for clinical treatment of pain hypersensitivity in bladder disorders but also in different other pathologies. |
| Databáze: | OpenAIRE |
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