A novel 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime compound is a potent Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1 and V1) receptor antagonist

Autor: Éva Szőke, Andrea Czompa, Maja Payrits, Péter Mátyus, Zoltán Sándor, Zs. Helyes, Ruth Deme, R. Ludmerczki, Éva Sághy
Rok vydání: 2015
Předmět:
0301 basic medicine
Cations
Divalent
Calcitonin Gene-Related Peptide
TRPV1
Drug Evaluation
Preclinical
CHO Cells
Pharmacology
Calcitonin gene-related peptide
Cell Line
03 medical and health sciences
Trigeminal ganglion
chemistry.chemical_compound
Transient receptor potential channel
0302 clinical medicine
Cricetulus
Transient Receptor Potential Channels
Isothiocyanates
Oximes
medicine
TRPM8
Animals
Enzyme Inhibitors
Rats
Wistar
Oxazoles
Neurons
Neurotransmitter Agents
Dose-Response Relationship
Drug
Molecular Structure
General Neuroscience
food and beverages
Sensory neuron
Trachea
030104 developmental biology
medicine.anatomical_structure
nervous system
chemistry
Biochemistry
Trigeminal Ganglion
Capsaicin
Sensory System Agents
Calcium
psychological phenomena and processes
030217 neurology & neurosurgery
Sensory nerve
Zdroj: Neuroscience. 324
ISSN: 1873-7544
Popis: Transient Receptor Potential Ankyrin 1 and Vanilloid 1 (TRPA1, TRPV1) ion channels expressed on nociceptive primary sensory neurons are important regulators of pain and inflammation. TRPA1 is activated by several inflammatory mediators including formaldehyde and methylglyoxal that are products of the semicarbazide-sensitive amine-oxidase enzyme (SSAO). SZV-1287 is a new 3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime SSAO inhibitor, its chemical structure is similar to other oxime derivatives described as TRPA1 antagonists. Therefore, we investigated its effects on TRPA1 and TRPV1 receptor activation on the cell bodies and peripheral terminals of primary sensory neurons and TRPA1 or TRPV1 receptor-expressing cell lines. Calcium influx in response to the TRPA1 agonist allyl-isothiocyanate (AITC) (200 μM) and the TRPV1 stimulator capsaicin (330 nM) in rat trigeminal neurons or TRPA1 and TRPV1 receptor-expressing cell lines was measured by microfluorimetry or radioactive (45)Ca(2+) uptake experiments. Calcitonin gene-related peptide (CGRP) release as the indicator of 100 μM AITC - or 100 nM capsaicin-induced peripheral sensory nerve terminal activation was measured by radioimmunoassay. SZV-1287 (100, 500 and 1000 nM) exerted a concentration-dependent significant inhibition on both AITC- and capsaicin-evoked calcium influx in trigeminal neurons and TRPA1 or TRPV1 receptor-expressing cell lines. It also significantly inhibited the TRPA1, but not the TRPV1 activation-induced CGRP release from the peripheral sensory nerve endings in a concentration-dependent manner. In contrast, the reference SSAO inhibitor LJP 1207 with a different structure had no effect on TRPA1 or TRPV1 activation in either model system. This is the first evidence that our novel oxime compound SZV-1287 originally developed as a SSAO inhibitor has a potent dual antagonistic action on TRPA1 and TRPV1 ion channels on primary sensory neurons.
Databáze: OpenAIRE
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