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首页> 美国卫生研究院文献>British Journal of Pharmacology and Chemotherapy >In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels – mirage or pot of gold?
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In pursuit of small molecule chemistry for calcium-permeable non-selective TRPC channels – mirage or pot of gold?

机译：追求钙可渗透的非选择性TRPC通道的小分子化学–海市or楼还是一桶金？

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摘要

The primary purpose of this review is to address the progress towards small molecule modulators of human Transient Receptor Potential Canonical proteins (TRPC1, TRPC3, TRPC4, TRPC5, TRPC6 and TRPC7). These proteins generate channels for calcium and sodium ion entry. They are relevant to many mammalian cell types including acinar gland cells, adipocytes, astrocytes, cardiac myocytes, cochlea hair cells, endothelial cells, epithelial cells, fibroblasts, hepatocytes, keratinocytes, leukocytes, mast cells, mesangial cells, neurones, osteoblasts, osteoclasts, platelets, podocytes, smooth muscle cells, skeletal muscle and tumour cells. There are broad-ranging positive roles of the channels in cell adhesion, migration, proliferation, survival and turning, vascular permeability, hypertrophy, wound-healing, hypo-adiponectinaemia, angiogenesis, neointimal hyperplasia, oedema, thrombosis, muscle endurance, lung hyper-responsiveness, glomerular filtration, gastrointestinal motility, pancreatitis, seizure, innate fear, motor coordination, saliva secretion, mast cell degranulation, cancer cell drug resistance, survival after myocardial infarction, efferocytosis, hypo-matrix metalloproteinase, vasoconstriction and vasodilatation. Known small molecule stimulators of the channels include hyperforin, genistein and rosiglitazone, but there is more progress with inhibitors, some of which have promising potency and selectivity. The inhibitors include 2-aminoethoxydiphenyl borate, 2-aminoquinolines, 2-aminothiazoles, fatty acids, isothiourea derivatives, naphthalene sulfonamides, N-phenylanthranilic acids, phenylethylimidazoles, piperazine/piperidine analogues, polyphenols, pyrazoles and steroids. A few of these agents are starting to be useful as tools for determining the physiological and pathophysiological functions of TRPC channels. We suggest that the pursuit of small molecule modulators for TRPC channels is important but that it requires substantial additional effort and investment before we can reap the rewards of highly potent and selective pharmacological modulators.
机译：这篇综述的主要目的是解决人类瞬态受体潜在规范蛋白（TRPC1，TRPC3，TRPC4，TRPC5，TRPC6和TRPC7）向小分子调节剂的发展。这些蛋白质产生钙和钠离子进入的通道。它们与许多哺乳动物细胞类型有关，包括腺泡细胞，脂肪细胞，星形胶质细胞，心肌细胞，耳蜗毛细胞，内皮细胞，上皮细胞，成纤维细胞，肝细胞，角质形成细胞，白细胞，肥大细胞，系膜细胞，神经元，成骨细胞，破骨细胞，血小板，足细胞，平滑肌细胞，骨骼肌和肿瘤细胞。这些通道在细胞黏附，迁移，增殖，存活和转向，血管通透性，肥大，伤口愈合，低脂联素血症，血管生成，新内膜增生，水肿，血栓形成，肌肉耐力，肺功能亢进方面具有广泛的积极作用。反应性，肾小球滤过，肠胃蠕动，胰腺炎，癫痫发作，先天恐惧，运动协调，唾液分泌，肥大细胞脱粒，癌细胞抗药性，心肌梗死后的生存，放血，低基质金属蛋白酶，血管收缩和血管舒张。已知的通道的小分子刺激物包括hyperforin，染料木黄酮和罗格列酮，但抑制剂的研究取得了更多进展，其中一些抑制剂具有强大的潜力和选择性。抑制剂包括2-氨基乙氧基二苯基硼酸酯，2-氨基喹啉，2-氨基噻唑，脂肪酸，异硫脲衍生物，萘磺酰胺，N-苯基邻氨基苯甲酸，苯基乙基咪唑，哌嗪/哌啶类似物，多酚，吡唑和类固醇。这些试剂中的一些已开始用作确定TRPC通道的生理和病理生理功能的工具。我们建议追求TRPC通道的小分子调节剂很重要，但是在获得高效和选择性药理调节剂的回报之前，还需要付出大量的额外努力和投资。

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