Schultz B D, Singh A K, Devor D C, Bridges R J
University of Pittsburgh School of Medicine, Pennsylvania, USA.
Physiol Rev. 1999 Jan;79(1 Suppl):S109-44. doi: 10.1152/physrev.1999.79.1.S109.
Pharmacology of CFTR Chloride Channel Activity. Physiol. Rev. 79, Suppl.: S109-S144, 1999. - The pharmacology of cystic fibrosis transmembrane conductance regulator (CFTR) is at an early stage of development. Here we attempt to review the status of those compounds that modulate the Cl- channel activity of CFTR. Three classes of compounds, the sulfonylureas, the disulfonic stilbenes, and the arylaminobenzoates, have been shown to directly interact with CFTR to cause channel blockade. Kinetic analysis has revealed the sulfonylureas and arylaminobenzoates interact with the open state of CFTR to cause blockade. Suggestive evidence indicates the disulfonic stilbenes act by a similar mechanism but only from the intracellular side of CFTR. Site-directed mutagenesis studies indicate the involvement of specific amino acid residues in the proposed transmembrane segment 6 for disulfonic stilbene blockade and segments 6 and 12 for arylaminobenzoate blockade. Unfortunately, these compounds (sulfonylureas, disulfonic stilbenes, arylaminobenzoate) also act at a number of other cellular sites that can indirectly alter the activity of CFTR or the transepithelial secretion of Cl-. The nonspecificity of these compounds has complicated the interpretation of results from cellular-based experiments. Compounds that increase the activity of CFTR include the alkylxanthines, phosphodiesterase inhibitors, phosphatase inhibitors, isoflavones and flavones, benzimidazolones, and psoralens. Channel activation can arise from the stimulation of the cAMP signal transduction cascade, the inhibition of inactivating enzymes (phosphodiesterases, phosphatases), as well as the direct binding to CFTR. However, in contrast to the compounds that block CFTR, a detailed understanding of how the above compounds increase the activity of CFTR has not yet emerged.
囊性纤维化跨膜传导调节因子（CFTR）氯离子通道活性的药理学。《生理学评论》79卷，增刊：S109 - S144，1999年。——囊性纤维化跨膜传导调节因子（CFTR）的药理学尚处于发展初期。在此，我们试图综述那些调节CFTR氯离子通道活性的化合物的研究现状。已证明三类化合物，即磺酰脲类、二磺酸芪类和芳氨基苯甲酸盐类，可直接与CFTR相互作用导致通道阻断。动力学分析表明，磺酰脲类和芳氨基苯甲酸盐类与CFTR的开放状态相互作用导致阻断。有暗示性证据表明，二磺酸芪类通过类似机制起作用，但仅从CFTR的细胞内侧起作用。定点诱变研究表明，特定氨基酸残基参与了二磺酸芪类阻断作用中拟议的跨膜片段6，以及芳氨基苯甲酸盐类阻断作用中的片段6和12。不幸的是，这些化合物（磺酰脲类、二磺酸芪类、芳氨基苯甲酸盐类）也作用于许多其他细胞位点，这些位点可间接改变CFTR的活性或氯离子的跨上皮分泌。这些化合物的非特异性使得基于细胞的实验结果解释变得复杂。增加CFTR活性的化合物包括烷基黄嘌呤类、磷酸二酯酶抑制剂、磷酸酶抑制剂、异黄酮和黄酮类、苯并咪唑酮类和补骨脂素类。通道激活可源于对环磷酸腺苷（cAMP）信号转导级联的刺激、对失活酶（磷酸二酯酶、磷酸酶）的抑制以及与CFTR的直接结合。然而，与阻断CFTR的化合物不同，目前尚未对上述化合物如何增加CFTR活性有详细的了解。
