A (+)‐Larixol Congener with High Affinity and Subtype Selectivity toward TRPC6,ChemMedChem

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A (+)‐Larixol Congener with High Affinity and Subtype Selectivity toward TRPC6
ChemMedChem ( IF 3.6 ) Pub Date : 2018-04-26 , DOI: 10.1002/cmdc.201800021
Stephanie Häfner ₁ , Finn Burg ₂ , Martina Kannler ₃ , Nicole Urban ₁ , Peter Mayer ₂ , Alexander Dietrich ₃ , Dirk Trauner _{2,

4} , Johannes Broichhagen _{2,

5} , Michael Schaefer ₁

Affiliation

Natural products have many health benefits, and their application can improve the quality of life. Recently, the diterpene (+)‐larixol and its acetylated congeners demonstrated selective inhibition of the second‐messenger‐gated cation channel transient receptor potential canonical 6 (TRPC6) over its close isoforms TRPC3 and TRPC7. Building on this knowledge, we expanded these findings by chemical diversification of (+)‐larixol mostly at position C6. Implementing high‐throughput Ca²⁺ FLIPR screening assays and electrophysiological patch‐clamp recordings, we showcase larixyl N‐methylcarbamate, termed SH045, as a compound with nanomolar affinity and 13‐fold subtype selectivity over TRPC3 in stably expressing HEK293 cells. Expanding on this finding, TRPC6 inhibition was also observed in rat pulmonary smooth muscle cells. Furthermore, treatment of isolated perfused lung preparations with SH045 led to a decrease in lung ischemia‐reperfusion edema (LIRE), a life‐threatening condition associated with TRPC6 that may occur after organ transplantation. Taken together, and given the inexpensive, straightforward, and scalable preparation of SH045, we report a TRPC6 blocker that holds promise for the translational treatment of LIRE.

中文翻译：

对TRPC6具有高亲和力和亚型选择性的（+）‐ Larixol同系物

天然产品具有许多健康益处，其应用可以改善生活质量。最近，二萜（+）-larixol及其乙酰化同源物证明了其紧密异构体TRPC3和TRPC7对第二信使门控阳离子通道瞬态受体电位正典6（TRPC6）的选择性抑制。在此知识的基础上，我们通过（+）‐ larixol的化学多样化（主要在C6位）扩展了这些发现。实施高通量Ca ²⁺ FLIPR筛查测定和电生理膜片钳记录，我们展示了Larixyl N-甲基氨基甲酸酯，称为SH045作为稳定表达的HEK293细胞中具有纳摩尔摩尔亲和力且相对于TRPC3具有13倍亚型选择性的化合物。扩大这一发现，在大鼠肺平滑肌细胞中也观察到了TRPC6抑制作用。此外，用SH045处理分离的灌注肺制品可降低肺缺血再灌注水肿（LIRE），这是在器官移植后可能发生的与TRPC6相关的危及生命的疾病。两者合计，并给予的廉价，简单和可扩展的准备SH045，我们报道了适用于里拉的平移处理承诺一个TRPC6拦截。

更新日期：2018-04-26

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