Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/221685
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | Highly functionalized β-lactams and 2-ketopiperazines as TRPM8 antagonists with antiallodynic activity |
Autor: | Bonache de Marcos, María Ángeles CSIC ORCID ; Martín-Escura, Cristina CSIC; Torre Martínez, R. de la; Medina, A.; González-Rodríguez, Sara; Francesch, Andrés; Cuevas, Carmen; Roa, A. M.; Fernández-Ballester, Gregorio CSIC; Ferrer-Montiel, Antonio CSIC ORCID; Fernández-Carvajal, Asia; González-Muñiz, Rosario CSIC ORCID | Fecha de publicación: | 2020 | Editor: | Springer Nature | Citación: | Scientific Reports 10 (2020) | Resumen: | 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 ?-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 Ca microfluorometry assay, and confirmed electrophysiologically for the best enantiopure ?-lactams 24a and 29a (IC, 1.4 and 0.8��M). 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 ?-lactams and KPs. ?-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. | Versión del editor: | http://dx.doi.org/10.1038/s41598-020-70691-x | URI: | http://hdl.handle.net/10261/221685 | DOI: | 10.1038/s41598-020-70691-x | Identificadores: | doi: 10.1038/s41598-020-70691-x issn:: 2045-2322 |
Aparece en las colecciones: | (IQM) Artículos |
Ficheros en este ítem:
Fichero | Descripción | Tamaño | Formato | |
---|---|---|---|---|
Artículo.pdf | 1,66 MB | Adobe PDF | Visualizar/Abrir |
CORE Recommender
PubMed Central
Citations
6
checked on 01-abr-2024
SCOPUSTM
Citations
6
checked on 23-abr-2024
WEB OF SCIENCETM
Citations
7
checked on 26-feb-2024
Page view(s)
157
checked on 24-abr-2024
Download(s)
168
checked on 24-abr-2024
Google ScholarTM
Check
Altmetric
Altmetric
Artículos relacionados:
NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.