title: 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.
abstract: 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.
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs-7624, Szigeti str. 12., Hungary; Szentágothai Research Centre, University of Pécs, Pécs-7624, Ifjúság str. 20., Hungary. Electronic address: payrits.maja@gmail.com.
authors.forename: M
authors.initials: M
authors.lastname: Payrits
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs-7624, Szigeti str. 12., Hungary; Szentágothai Research Centre, University of Pécs, Pécs-7624, Ifjúság str. 20., Hungary. Electronic address: saghyeva@gmail.com.
authors.forename: É
authors.initials: É
authors.lastname: Sághy
authors.affiliation: Department of Organic Chemistry, University of Semmelweis, Budapest-1092, Hőgyes Endre str. 7., Hungary. Electronic address: matyus.peter@pharma.semmelweis-univ.hu.
authors.forename: P
authors.initials: P
authors.lastname: Mátyus
authors.affiliation: Department of Organic Chemistry, University of Semmelweis, Budapest-1092, Hőgyes Endre str. 7., Hungary. Electronic address: czompa.andrea@pharma.semmelweis-univ.hu.
authors.forename: A
authors.initials: A
authors.lastname: Czompa
authors.affiliation: Department of Organic Chemistry, University of Semmelweis, Budapest-1092, Hőgyes Endre str. 7., Hungary. Electronic address: ludmerczki.robert@pharma.semmelweis-univ.hu.
authors.forename: R
authors.initials: R
authors.lastname: Ludmerczki
authors.affiliation: Department of Organic Chemistry, University of Semmelweis, Budapest-1092, Hőgyes Endre str. 7., Hungary. Electronic address: deme.ruth@pharma.semmelweis-univ.hu.
authors.forename: R
authors.initials: R
authors.lastname: Deme
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs-7624, Szigeti str. 12., Hungary. Electronic address: zoltan.sandor@aok.pte.hu.
authors.forename: Z
authors.initials: Z
authors.lastname: Sándor
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs-7624, Szigeti str. 12., Hungary; Szentágothai Research Centre, University of Pécs, Pécs-7624, Ifjúság str. 20., Hungary; MTA-PTE Chronic Pain Research Group, Pécs-7624, Szigeti str. 12., Hungary. Electronic address: zsuzsanna.helyes@aok.pte.hu.
authors.forename: Zs
authors.initials: Z
authors.lastname: Helyes
authors.affiliation: Department of Pharmacology and Pharmacotherapy, Faculty of Medicine, University of Pécs, Pécs-7624, Szigeti str. 12., Hungary; Szentágothai Research Centre, University of Pécs, Pécs-7624, Ifjúság str. 20., Hungary; MTA-PTE Chronic Pain Research Group, Pécs-7624, Szigeti str. 12., Hungary. Electronic address: eva.szoke@aok.pte.hu.
authors.forename: É
authors.initials: É
authors.lastname: Szőke
mesh_terms: D000818:Animals; D016466:CHO Cells; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002211:Capsaicin / Q000494:pharmacology; D002413:Cations, Divalent / Q000378:metabolism; D002460:Cell Line; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D017879:Isothiocyanates / Q000494:pharmacology; D015394:Molecular Structure; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D010080:Oxazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010091:Oximes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D017208:Rats, Wistar; D018689:Sensory System Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D014132:Trachea / Q000294:innervation; D050051:Transient Receptor Potential Channels / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012668:Trigeminal Ganglion / Q000187:drug effects / Q000502:physiology
chemical_list: C000613315:3-(4,5-diphenyl-1,3-oxazol-2-yl)propanal oxime; D002413:Cations, Divalent; D004791:Enzyme Inhibitors; D017879:Isothiocyanates; D018377:Neurotransmitter Agents; D010080:Oxazoles; D010091:Oximes; D018689:Sensory System Agents; D050051:Transient Receptor Potential Channels; C108790:acetyl isothiocyanate; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D002118:Calcium
keywords: SZV-1287; Transient Receptor Potential Ankyrin 1 and Vanilloid 1 receptors; allyl-isothiocyanate; capsaicin; semicarbazide-sensitive amine-oxidase; sensory neuron