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Phenylalanine-Derived β-Lactam TRPM8 Modulators. Configuration Effect on the Antagonist Activity
- Source :
- International Journal of Molecular Sciences, Digital.CSIC: Repositorio Institucional del CSIC, Consejo Superior de Investigaciones Científicas (CSIC), Volume 22, Issue 5, International Journal of Molecular Sciences, Vol 22, Iss 2370, p 2370 (2021), Digital.CSIC. Repositorio Institucional del CSIC, instname
- Publication Year :
- 2020
-
Abstract
- 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-[(30-phenyl-20- dibenzylamino)prop-10-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,20R > 3S,4S,20R =3R,4R,20S > 3S,4S,20S, 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.<br />This research was funded by the Spanish Ministerio de Ciencia y Universidades (MICYUFEDER, RTI2018-097189-C2-1 to A.F.-M. and A.F.-C., and RTI2018-097189-C2-2 to R.G.M.), Comunidad de Madrid (IND2017/BMD7673 to R.G.-M.) and the Spanish National Research Council (CSIC, 201980E030 to R.G.-M.).
- Subjects :
- Ca
Phenylalanine
β–lactams
lcsh:Chemistry
chemistry.chemical_compound
TRPM
Ganglia, Spinal
lcsh:QH301-705.5
Ca2+ microfluorimetry
Spectroscopy
Cells, Cultured
Neurons
antagonists
Chemistry
β–lactam
General Medicine
Computer Science Applications
Molecular Docking Simulation
Lactam
TRPM Cation Channel
TRPM8
Patch-Clamp
Stereochemistry
2+
TRPM Cation Channels
microfluorimetry
beta-Lactams
Catalysis
Article
Inorganic Chemistry
Structure-Activity Relationship
Animals
Absolute configuration
Patch clamp
Physical and Theoretical Chemistry
Molecular Biology
IC50
Ion channel
Animal
Patch- Clamp
Organic Chemistry
Antagonist
Neuron
Rats
absolute configuration
lcsh:Biology (General)
lcsh:QD1-999
Rat
Antagonists
Subjects
Details
- ISSN :
- 14220067
- Volume :
- 22
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- International journal of molecular sciences
- Accession number :
- edsair.doi.dedup.....e534cd60d980af86e9cf0cefed712035