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Title

Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity

AuthorsBonache de Marcos, María Ángeles CSIC ORCID ; Llabrés, Pedro Juan; Martín-Escura, Cristina; Torre-Martínez, Roberto de la; Medina-Peris, Alicia; Butrón, Laura; Gómez-Monterrey, Isabel; Roa, Ana María; Fernández-Ballester, Gregorio; Ferrer-Montiel, Antonio; Fernández-Carvajal, Asia; González-Muñiz, Rosario CSIC ORCID
KeywordsTRPM8
Antagonists
β–lactams
Absolute configuration
Ca2+ microfluorimetry
Patch- Clamp
Issue Date2021
PublisherMultidisciplinary Digital Publishing Institute
CitationInternational Journal of Molecular Sciences 22 : 2370 (2021)
AbstractTransient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ nonselective ion channel implicated in a variety of pathological conditions, including cancer, inflammatory and neuropathic pain. In previous works we identified a family of chiral, highly hydrophobic β–lactam derivatives, and began to intuit a possible effect of the stereogenic centers on the antagonist activity. To investigate the influence of configuration on the TRPM8 antagonist properties, here we prepare and characterize four possible diastereoisomeric derivatives of 4-benzyl-1-[(3’-phenyl- 2’-dibenzylamino)prop-1’-yl]-4-benzyloxycarbonyl-3-methyl-2-oxoazetidine. In microfluorography assays, all isomers were able to reduce the menthol-induced cell Ca2+ entry to larger or lesser extent. Potency follows the order 3R,4R,2’R > 3S,4S,2’R ≅ 3R,4R,2’S > 3S,4S,2’S, with the most potent diastereoisomer showing a half inhibitory concentration (IC50) in the low nanomolar range, confirmed by Patch-Clamp electrophysiology experiments. All four compounds display high receptor selectivity against other members of the TRP family. Furthermore, in primary cultures of rat dorsal root ganglion (DRG) neurons, the most potent diastereoisomers do not produce any alteration in neuronal excitability, indicating their high specificity for TRPM8 channels. Docking studies positioned these β-lactams at different subsites by the pore zone, suggesting a different mechanism than the known N-(3-aminopropyl)-2-[(3-methylphenyl)methoxy]-N-(2-thienylmethyl)-benzamide (AMTB) antagonist.
Publisher version (URL)https://doi.org/10.3390/ijms22052370
URIhttp://hdl.handle.net/10261/240941
DOIhttp://dx.doi.org/10.3390/ijms22052370
ISSN1661-6596
E-ISSN1422-0067
Appears in Collections:(IQM) Artículos
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