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.

中文翻译：

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一种新型的3-（4,5-二苯基-1,3-恶唑-2-基）丙醛肟化合物是一种有效的瞬态受体电位锚蛋白1和香草醛1（TRPA1和V1）受体拮抗剂。

在伤害性初级感觉神经元上表达的瞬时受体电位锚蛋白1和香草酸1（TRPA1，TRPV1）离子通道是疼痛和炎症的重要调节剂。TRPA1被几种炎症介质激活，这些介质包括对氨基脲敏感的胺氧化酶（SSAO）的甲醛和甲基乙二醛。SZV-1287是一种新型的3-（4,5-二苯基-1,3-恶唑-2-基）丙醛肟SSAO抑制剂，其化学结构与其他被描述为TRPA1拮抗剂的肟衍生物相似。因此，我们调查了其对原代感觉神经元和TRPA1或TRPV1受体表达细胞系的细胞体和外围末端上TRPA1和TRPV1受体激活的影响。通过微荧光法或放射性（45）Ca测量了大鼠三叉神经元或表达TRPA1和TRPV1受体的细胞系中对TRPA1激动剂烯丙基异硫氰酸烯丙酯（AITC）（200μM）和TRPV1刺激辣椒素（330 nM）的钙内流（2+）摄取实验。通过放射免疫测定法测定降钙素基因相关肽（CGRP）的释放作为100μMAITC或100 nM辣椒素诱导的周围感觉神经末梢活化的指标。SZV-1287（100、500和1000 nM）对三叉神经元和表达TRPA1或TRPV1受体的细胞系中AITC和辣椒素引起的钙内流均具有浓度依赖性的显着抑制作用。它也以浓度依赖的方式显着抑制TRPA1，但不抑制TRPV1激活诱导的CGRP从周围感觉神经末梢释放。相反，在任何一个模型系统中，具有不同结构的参比SSAO抑制剂LJP 1207对TRPA1或TRPV1的活化均无影响。这是第一个证据，证明我们最初开发为SSAO抑制剂的新型肟化合物SZV-1287对初级感觉神经元上的TRPA1和TRPV1离子通道具有有效的双重拮抗作用。