Simple 2,4-Diacylphloroglucinols as Classic Transient Receptor Potential-6 Activators-Identification of a Novel Pharmacophore
Simple 2,4-Diacylphloroglucinols as Classic Transient Receptor Potential-6 Activators-Identification of a Novel Pharmacophore
复制标题
DOI：
10.1124/mol.109.057513
复制
发表时间：
2010-03-01
影响因子：
3.6
通讯作者：
Mueller, W. E.
中科院分区：
文献类型：
--
作者：
Leuner, K.;Heiser, J. H.;Mueller, W. E.
天然存在的酰化间苯三酚衍生物贯叶金丝桃素最近被鉴定为第一个特异性典型瞬时受体电位6（TRPC 6）激活剂。贯叶连翘素是圣约翰草的主要抗抑郁成分，其通过TRPC 6通道激活介导其抗抑郁样性质。然而，其用于激活TRPC 6通道的药效团部分是未知的。我们假设间苯三酚部分可能是贯叶金丝桃素的基本药效团，其活性特征可能是由于与TRPC 3，TRPC 6和TRPC 7的内源性非选择性激活剂二酰基甘油（DAG）的结构相似。因此，测试了一些2-酰基和2，4-二酰基间苯三酚的贯叶金丝桃素样活性特征。我们使用一系列实验模型来研究TRPC 6激活的所有功能方面，包括离子通道记录、Ca 2+成像、神经突生长和突触体摄取的抑制。间苯三酚本身在我们所有的测定中是无活性的，这也是2-酰基间苯三酚的情况。对于TRPC 6激活，在间苯三酚部分中存在两个对称的酰基取代与适当的烷基链似乎是一个必不可少的先决条件。这些化合物在所有测定中的效力与贯叶金丝桃素激活TRPC 6通道的效力相当。最后，使用基于结构的建模技术，我们提出了一个结合模式hyperforin的TRPC 6。基于这种建模方法，我们提出，DAG是能够激活TRPC 3，TRPC 6，和TRPC 7，因为更高的灵活性内的DAG的化学结构相比，而刚性结构的贯叶金丝桃素和2，4-二酰基间苯三酚衍生物。
The naturally occurring acylated phloroglucinol derivative hyperforin was recently identified as the first specific canonical transient receptor potential-6 (TRPC6) activator. Hyperforin is the major antidepressant component of St. John's wort, which mediates its antidepressant-like properties via TRPC6 channel activation. However, its pharmacophore moiety for activating TRPC6 channels is unknown. We hypothesized that the phloroglucinol moiety could be the essential pharmacophore of hyperforin and that its activity profile could be due to structural similarities with diacylglycerol (DAG), an endogenous nonselective activator of TRPC3, TRPC6, and TRPC7. Accordingly, a few 2-acyl and 2,4-diacylphloroglucinols were tested for their hyperforin-like activity profiles. We used a battery of experimental models to investigate all functional aspects of TRPC6 activation, including ion channel recordings, Ca2+ imaging, neurite outgrowth, and inhibition of synaptosomal uptake. Phloroglucinol itself was inactive in all of our assays, which was also the case for 2-acylphloroglucinols. For TRPC6 activation, the presence of two symmetrically acyl-substitutions with appropriate alkyl chains in the phloroglucinol moiety seems to be an essential prerequisite. Potencies of these compounds in all assays were comparable with that of hyperforin for activating the TRPC6 channel. Finally, using structure-based modeling techniques, we suggest a binding mode for hyperforin to TRPC6. Based on this modeling approach, we propose that DAG is able to activate TRPC3, TRPC6, and TRPC7 because of higher flexibility within the chemical structure of DAG compared with the rather rigid structures of hyperforin and the 2,4-diacylphloroglucinol derivatives.