Dasgupta Pooja, Gűnther Thomas, Schulz Stefan
Institute of Pharmacology and Toxicology, Jena University Hospital, Friedrich Schiller University Jena, 07747 Jena, Germany.
Life (Basel). 2021 Oct 12;11(10):1075. doi: 10.3390/life11101075.
Veldoreotide, a somatostatin analogue, binds to the somatostatin receptors (SSTR) 2, 4, and 5. The current aim was to assess its pharmacological activity as an SSTR4 agonist. G-protein signaling was assessed using a fluorescence-based membrane potential assay in human embryonic kidney 293 (HEK293) cells stably co-expressing G-protein-coupled inwardly rectifying potassium 2 channels and the individual SSTR2, SSTR4, and SSTR5, and in human BON-1 cells stably expressing these SSTRs. Veldoreotide effects on chromogranin A (CgA) secretion and cell proliferation were examined in BON-1 cells. In HEK293 transfected cells, veldoreotide showed a high efficacy for activating the SSTR4; octreotide and pasireotide had little activity (E, 99.5% vs. 27.4% and 52.0%, respectively). Veldoreotide also activated SSTR2 and SSTR5 (E, 98.4% and 96.9%, respectively). In BON-1 cells, veldoreotide activated SSTR2, SSTR4, and SSTR5 with high potency and efficacy. CgA secretion was decreased to a greater degree in the BON-1 cells expressing SSTR4 versus the cells expressing SSTR2 and SSTR5 (65.3% vs. 80.3% and 77.6%, respectively). In the BON-1 cells expressing SSTR4, veldoreotide inhibited cell proliferation more than somatostatin SS-14 (71.2% vs. 79.7%) and to a similar extent as the SSTR4 agonist J-2156 in the presence of SSTR2 and SSTR5 antagonists. Veldoreotide is a full agonist of SSTR2, SSTR4, and SSTR5.
维得瑞otide是一种生长抑素类似物，可与生长抑素受体（SSTR）2、4和5结合。当前的目的是评估其作为SSTR4激动剂的药理活性。使用基于荧光的膜电位测定法，在稳定共表达G蛋白偶联内向整流钾通道2以及单独的SSTR2、SSTR4和SSTR5的人胚肾293（HEK293）细胞中，以及在稳定表达这些SSTR的人BON-1细胞中评估G蛋白信号传导。在BON-1细胞中检测维得瑞otide对嗜铬粒蛋白A（CgA）分泌和细胞增殖的影响。在转染的HEK293细胞中，维得瑞otide显示出激活SSTR4的高效能；奥曲肽和帕西瑞肽活性很小（效能分别为99.5%、27.4%和52.0%）。维得瑞otide还激活了SSTR2和SSTR5（效能分别为98.4%和96.9%）。在BON-1细胞中，维得瑞otide以高效能和高效激活SSTR2、SSTR4和SSTR5。与表达SSTR2和SSTR5的细胞相比，表达SSTR4的BON-1细胞中CgA分泌减少的程度更大（分别为65.3%、80.3%和77.6%）。在表达SSTR4的BON-1细胞中，维得瑞otide比生长抑素SS-14更能抑制细胞增殖（71.2%对79.7%），并且在存在SSTR2和SSTR5拮抗剂的情况下，其抑制程度与SSTR4激动剂J-2156相似。维得瑞otide是SSTR2、SSTR4和SSTR5的完全激动剂。
