Hedner Erik, Sjögren Martin, Frändberg Per-Anders, Johansson Tobias, Göransson Ulf, Dahlström Mia, Jonsson Per, Nyberg Fred, Bohlin Lars
Division of Pharmacognosy, Department of Medicinal Chemistry, Biomedical Centre, Uppsala University, SE-751 23 Uppsala, Sweden.
J Nat Prod. 2006 Oct;69(10):1421-4. doi: 10.1021/np0601760.
The brominated cyclodipeptides barettin (cyclo[(6-bromo-8-entryptophan)arginine]) and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose-dependent manner in concentrations ranging from 0.5 to 25 microM. To further establish the molecular target and mode of action of these compounds, we investigated their affinity to human serotonin receptors. The tryptophan residue in the barettins resembles that of endogenous serotonin [5-hydroxytryptamine]. A selection of human serotonin receptors, including representatives from all subfamilies (1-7), were transfected into HEK-293 cells. Barettin selectively interacted with the serotonin receptors 5-HT2A, 5-HT2C, and 5-HT4 at concentrations close to that of endogenous serotonin, with the corresponding Ki values being 1.93, 0.34, and 1.91 microM, respectively. 8,9-Dihydrobarettin interacted exclusively with the 5-HT2C receptor with a Ki value of 4.63 microM; it failed to show affinity to 5-HT2A and 5-HT4, indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins.
从海洋海绵巴氏地海绵中分离出的溴化环二肽巴雷汀（环[（6-溴-8-对映体色氨酸）精氨酸]）和8,9-二氢巴雷汀（环[（6-溴色氨酸）精氨酸]）先前已被证明能以剂量依赖方式抑制藤壶幼虫的附着，浓度范围为0.5至25微摩尔。为了进一步确定这些化合物的分子靶点和作用方式，我们研究了它们与人血清素受体的亲和力。巴雷汀中的色氨酸残基与内源性血清素[5-羟色胺]的相似。将一系列人血清素受体，包括所有亚家族（1-7）的代表，转染到HEK-293细胞中。巴雷汀在接近内源性血清素的浓度下与血清素受体5-HT2A、5-HT2C和5-HT4选择性相互作用，相应的Ki值分别为1.93、0.34和1.91微摩尔。8,9-二氢巴雷汀仅与5-HT2C受体相互作用，Ki值为4.63微摩尔；它对5-HT2A和5-HT4没有亲和力，这表明色氨酸和精氨酸残基之间的双键在与受体蛋白的相互作用中起重要作用。
