TRP channels are important pharmacological targets in physiopathology. TRPV2 plays distinct roles in cardiac and neuromuscular function, immunity, and metabolism, and is associated with pathologies like muscular dystrophy and cancer. However, TRPV2 pharmacology is unspecific and scarce at best. Using in silico similarity-based chemoinformatics we obtained a set of 270 potential hits for TRPV2 categorized into families based on chemical nature and similarity. Docking the compounds on available rat TRPV2 structures allowed the clustering of drug families in specific ligand binding sites. Starting from a probenecid docking pose in the piperlongumine binding site and using a Gaussian accelerated molecular dynamics approach we have assigned a putative probenecid binding site. In parallel, we measured the EC50 of 7 probenecid derivatives on TRPV2 expressed in Pichia pastoris using a novel medium-throughput Ca²⁺ influx assay in yeast membranes together with an unbiased and unsupervised data analysis method. We found that 4-(piperidine-1-sulfonyl)-benzoic acid had a better EC50 than probenecid, which is one of the most specific TRPV2 agonists to date. Exploring the TRPV2-dependent anti-hypertensive potential in vivo, we found that 4-(piperidine-1-sulfonyl)-benzoic acid shows a sex-biased vasodilator effect producing larger vascular relaxations in female mice. Overall, this study expands the pharmacological toolbox for TRPV2, a widely expressed membrane protein and orphan drug target.

TRP 通道是病理生理学中重要的药理学靶点。TRPV2 在心脏和神经肌肉功能、免疫和代谢中发挥着独特的作用，并且与肌营养不良症和癌症等病理相关。然而，TRPV2 药理学并不具有特异性，而且充其量也是稀缺的。使用基于计算机相似性的化学信息学，我们获得了一组 270 个 TRPV2 潜在命中，根据化学性质和相似性分类为家族。将化合物与可用的大鼠 TRPV2 结构对接，使药物家族在特定的配体结合位点聚集。从胡椒长明结合位点中的丙磺舒对接姿势开始，并使用高斯加速分子动力学方法，我们指定了假定的丙磺舒结合位点。同时，我们使用酵母膜中新型中等通量 Ca 2+ 内流测定以及无偏且无监督的数据分析方法，测量了 7 种丙磺舒衍生物对毕赤酵母中表达的TRPV2的^EC50。我们发现 4-(哌啶-1-磺酰基)-苯甲酸比丙磺舒具有更好的 EC50，丙磺舒是迄今为止最具特异性的 TRPV2 激动剂之一。在探索TRPV2依赖性体内抗高血压潜力时，我们发现4-(哌啶-1-磺酰基)-苯甲酸表现出性别偏向的血管舒张作用，在雌性小鼠中产生更大的血管舒张作用。总体而言，这项研究扩展了 TRPV2（一种广泛表达的膜蛋白和孤儿药靶点）的药理学工具箱。