Clotrimazole-Based Modulators of the TRPM3 Ion Channel Reveal Narrow Structure–Activity Relationship,ACS Chemical Biology

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Clotrimazole-Based Modulators of the TRPM3 Ion Channel Reveal Narrow Structure–Activity Relationship
ACS Chemical Biology ( IF 3.5 ) Pub Date : 2023-02-10 , DOI: 10.1021/acschembio.2c00672
Jan Pascal Kahler ₁ , Vincenzo Davide Aloi _{2,

3,

4} , Julia Miedes Aliaga ₁ , Sara Kerselaers _{2,

3} , Thomas Voets _{2,

3} , Joris Vriens ₄ , Steven H L Verhelst _{1,

5} , Marta Barniol-Xicota ₁

Affiliation

TRPM3 is an ion channel that is highly expressed in nociceptive neurons and plays a key role in pain perception. In the presence of the endogenous TRPM3 ligand, pregnenolone sulfate (PS), the antifungal compound clotrimazole (Clt) augments Ca²⁺ signaling and opens a non-canonical pore, permeable to Na⁺, which aggravates TRPM3-induced pain. To date, little is known about structural features that govern the Clt modulatory effect of TRPM3. Here, we synthesized and evaluated several Clt analogues in order to gain insights into their structure–activity relationship. Our results reveal a tight SAR with the three phenyl rings on the trityl moiety being essential for the activity, as well as the presence of fluorine or chlorine substituents on the trityl group. Imidazole as a heterocycle is also necessary for activity. Interestingly, we identified a pentafluoro-trityl analogue (29a) that is able to act as a TRPM3 agonist in the absence of PS. The compounds we report in this work will be useful tools for the further study of TRPM3 modulation and its effect on pain perception.

中文翻译：

基于克霉唑的 TRPM3 离子通道调节剂揭示了狭窄的结构-活性关系

TRPM3 是一种在伤害性神经元中高表达的离子通道，在疼痛感知中起着关键作用。在存在内源性 TRPM3 配体、硫酸孕烯醇酮 (PS) 的情况下，抗真菌化合物克霉唑 (Clt) 增强 Ca ²⁺信号并打开一个可渗透 Na ^{+的非规范孔}，这会加重 TRPM3 引起的疼痛。迄今为止，关于控制 TRPM3 的 Clt 调节作用的结构特征知之甚少。在这里，我们合成并评估了几种 Clt 类似物，以深入了解它们的构效关系。我们的结果揭示了紧密的 SAR，三苯甲基部分上的三个苯环对于活性至关重要，并且三苯甲基上存在氟或氯取代基。咪唑作为杂环也是活性所必需的。有趣的是，我们发现了一种五氟三苯甲基类似物 ( 29a )，它能够在没有 PS 的情况下充当 TRPM3 激动剂。我们在这项工作中报告的化合物将成为进一步研究 TRPM3 调制及其对痛觉的影响的有用工具。

更新日期：2023-02-10

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