Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol-sensitive TRPC cation channels
Discovery and pharmacological characterization of a novel potent inhibitor of diacylglycerol-sensitive TRPC cation channels
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DOI：
10.1111/bph.13151
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发表时间：
2015-07-01
影响因子：
7.3
通讯作者：
Struebing, C.
中科院分区：
文献类型：
--
作者：
Maier, T.;Follmann, M.;Struebing, C.
背景和目的典型阳离子通道瞬时受体电位（TRPC）6与多种病理学相关，包括局灶节段性肾小球硬化、肺动脉高压和缺血再灌注诱导的肺水肿。本论文的目的是寻找TRPC 6通道的抑制剂并研究其潜在的治疗作用。实验方法设计并合成了一个TRPC通道抑制剂库。通过测量细胞内Ca2+水平来评估化合物的活性。通过全细胞膜片钳技术进一步表征了先导化合物SAR 7334。SAR7334对急性缺氧性肺血管收缩（HPV）和全身BP的影响进行了研究。Key ResultsSAR7334抑制TRPC6、TRPC3和TRPC7介导的Ca2+内流进入细胞，IC（50）为9.5、282和226 nM，而TRPC4和TRPC5介导的Ca2+内流不受影响。膜片钳实验证实，该化合物阻断TRPC 6电流，IC50为7.9 nM。此外，SAR7334在小鼠离体灌注肺中抑制TRPC6依赖性急性HPV。SAR7334的药代动力学研究表明，该化合物适合长期口服给药。在最初的短期研究中，SAR7334没有改变自发性高血压大鼠（SHR）的平均动脉压。结论和含义我们的研究结果证实了TRPC 6通道在缺氧性肺血管调节中的作用，并表明这些通道不太可能在SHR的血压调节中发挥重要作用。SAR7334是一种新型、高效和生物可利用的TRPC 6通道抑制剂，为研究体内TRPC通道功能开辟了新的机会。
Background and PurposeThe cation channel transient receptor potential canonical (TRPC) 6 has been associated with several pathologies including focal segmental glomerulosclerosis, pulmonary hypertension and ischaemia reperfusion-induced lung oedema. We set out to discover novel inhibitors of TRPC6 channels and investigate the therapeutic potential of these agents.Experimental ApproachA library of potential TRPC channel inhibitors was designed and synthesized. Activity of the compounds was assessed by measuring intracellular Ca2+ levels. The lead compound SAR7334 was further characterized by whole-cell patch-clamp techniques. The effects of SAR7334 on acute hypoxic pulmonary vasoconstriction (HPV) and systemic BP were investigated.Key ResultsSAR7334 inhibited TRPC6, TRPC3 and TRPC7-mediated Ca2+ influx into cells with IC(50)s of 9.5, 282 and 226 nM, whereas TRPC4 and TRPC5-mediated Ca2+ entry was not affected. Patch-clamp experiments confirmed that the compound blocked TRPC6 currents with an IC50 of 7.9 nM. Furthermore, SAR7334 suppressed TRPC6-dependent acute HPV in isolated perfused lungs from mice. Pharmacokinetic studies of SAR7334 demonstrated that the compound was suitable for chronic oral administration. In an initial short-term study, SAR7334 did not change mean arterial pressure in spontaneously hypertensive rats (SHR).Conclusions and ImplicationsOur results confirm the role of TRPC6 channels in hypoxic pulmonary vasoregulation and indicate that these channels are unlikely to play a major role in BP regulation in SHR. SAR7334 is a novel, highly potent and bioavailable inhibitor of TRPC6 channels that opens new opportunities for the investigation of TRPC channel function in vivo.