Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity
| Autor: | Rosario González-Muñiz, Carmen Cuevas, M. Angeles Bonache, Roberto de la Torre Martínez, Sara González-Rodríguez, Ana María Roa, Alicia Medina, Antonio Ferrer-Montiel, Asia Fernández-Carvajal, Gregorio Fernández-Ballester, Cristina Martín-Escura, Andrés Francesch |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Male Models Molecular Patch-Clamp Techniques Drug Evaluation Preclinical lcsh:Medicine Medicinal chemistry Pharmacology Piperazines Transient receptor potential channel Mice 0302 clinical medicine lcsh:Science Analgesics Multidisciplinary Molecular Structure Chemistry Peripheral Nervous System Diseases Chemical biology Cold Temperature Molecular Docking Simulation Oxaliplatin Allodynia Hyperalgesia Ion channels Cytophotometry medicine.symptom TRPM Cation Channels Antineoplastic Agents beta-Lactams Article 03 medical and health sciences Structure-Activity Relationship Cell Line Tumor TRPM8 medicine Animals Drug discovery and development Computer Simulation Binding site IC50 lcsh:R Antagonist 030104 developmental biology Tumor progression Cell culture lcsh:Q 030217 neurology & neurosurgery Transient receptor potential channels |
| Zdroj: | Scientific Reports, Vol 10, Iss 1, Pp 1-15 (2020) Scientific Reports Digital.CSIC. Repositorio Institucional del CSIC instname |
| ISSN: | 2045-2322 |
| DOI: | 10.1038/s41598-020-70691-x |
| Popis: | The cool sensor transient receptor potential melastatin channel 8 (TRPM8) is highly expressed in trigeminal and dorsal root ganglia, playing a key role in cold hypersensitivity associated to different peripheral neuropathies. Moreover, these channels are aberrantly expressed in different cancers, and seem to participate in tumor progression, survival and invasion. Accordingly, the search for potent and selective TRPM8 modulators attracted great interest in recent years. We describe new heterocyclic TRPM8 antagonist chemotypes derived from N-cloroalkyl phenylalaninol-Phe conjugates. The cyclization of these conjugates afforded highly substituted β-lactams and/or 2-ketopiperazine (KP) derivatives, with regioselectivity depending on the N-chloroalkyl group and the configuration. These derivatives behave as TRPM8 antagonists in the Ca2+ microfluorometry assay, and confirmed electrophysiologically for the best enantiopure β-lactams 24a and 29a (IC50, 1.4 and 0.8 µM). Two putative binding sites by the pore zone, different from those found for typical agonists and antagonists, were identified by in silico studies for both β-lactams and KPs. β-Lactams 24a and 29a display antitumor activity in different human tumor cell lines (micromolar potencies, A549, HT29, PSN1), but correlation with TRPM8 expression could not be established. Additionally, compound 24a significantly reduced cold allodynia in a mice model of oxaliplatin-induced peripheral neuropathy. |
| Databáze: | OpenAIRE |
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