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Open AccessArticle

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

1
Instituto de Química Médica (IQM-CSIC), Juan de la Cierva 3, 28006 Madrid, Spain
2
Alodia Farmacéutica SL, Santiago Grisolia 2, Tres Cantos, 28760 Madrid, Spain
3
IDiBE, Universidad Miguel Hernández, Avda. de la Universidad s/n, 03202 Elche, Spain
4
Department of Pharmacy, University Federico II of Naples, 80131 Naples, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Ludmilla A. Morozova-Roche
Int. J. Mol. Sci. 2021, 22(5), 2370; https://doi.org/10.3390/ijms22052370
Received: 15 December 2020 / Revised: 22 February 2021 / Accepted: 23 February 2021 / Published: 27 February 2021
(This article belongs to the Special Issue Membrane Channels in Health and Diseases)
Transient receptor potential cation channel subfamily M member 8 (TRPM8) is a Ca2+ non-selective 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. View Full-Text
Keywords: TRPM8; antagonists; β–lactams; absolute configuration; Ca2+ microfluorimetry; Patch-Clamp TRPM8; antagonists; β–lactams; absolute configuration; Ca2+ microfluorimetry; Patch-Clamp
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MDPI and ACS Style

Bonache, M.Á.; Llabrés, P.J.; Martín-Escura, C.; De la Torre-Martínez, R.; Medina-Peris, A.; Butrón, L.; Gómez-Monterrey, I.; Roa, A.M.; Fernández-Ballester, G.; Ferrer-Montiel, A.; Fernández-Carvajal, A.; González-Muñiz, R. Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity. Int. J. Mol. Sci. 2021, 22, 2370. https://doi.org/10.3390/ijms22052370

AMA Style

Bonache MÁ, Llabrés PJ, Martín-Escura C, De la Torre-Martínez R, Medina-Peris A, Butrón L, Gómez-Monterrey I, Roa AM, Fernández-Ballester G, Ferrer-Montiel A, Fernández-Carvajal A, González-Muñiz R. Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity. International Journal of Molecular Sciences. 2021; 22(5):2370. https://doi.org/10.3390/ijms22052370

Chicago/Turabian Style

Bonache, María Á.; Llabrés, Pedro J.; Martín-Escura, Cristina; De la Torre-Martínez, Roberto; Medina-Peris, Alicia; Butrón, Laura; Gómez-Monterrey, Isabel; Roa, Ana M.; Fernández-Ballester, Gregorio; Ferrer-Montiel, Antonio; Fernández-Carvajal, Asia; González-Muñiz, Rosario. 2021. "Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity" Int. J. Mol. Sci. 22, no. 5: 2370. https://doi.org/10.3390/ijms22052370

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