Discovery of a novel non-peptide somatostatin agonist with SST4 selectivity
Discovery of a novel non-peptide somatostatin agonist with SST4 selectivity
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DOI：
10.1021/ja973325x
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发表时间：
1998-02-25
影响因子：
15
通讯作者：
Stidsen, C
中科院分区：
文献类型：
--
作者：
Ankersen, M;Crider, M;Stidsen, C
新的非肽化合物的发现与肽激素生长抑素（SST）受体高亲和力描述。这些化合物在哺乳动物细胞中分别表达的五种人类SST受体亚型中进行了亲和力测试。化合物NNC 26-9100对SST4的K-i为6 nM，对SST4的选择性是SST1、SST2、SST3和SST5的100倍以上。NNC 26-9100与SST相互作用的竞争结合研究和Scatchard分析显示，SST4具有特异性。此外，NNC 26-9100在多种G蛋白偶联受体上对SST4具有高度选择性，对M-1毒蕈碱乙酰胆碱受体和D-3多巴胺受体分别具有约500 nM和1000 nM的亲和力。最后，我们发现NNC 26-9100完全抑制福斯克林诱导的3′，5′-环单磷酸腺苷在幼鼠肾细胞中的积累，表达人SST4受体，EC50为2 nM。
The discovery of novel non-peptide compounds with a high affinity for the peptide hormone somatostatin (SST) receptor is described. The compounds were tested for affinity at five human SST receptor subtypes individually expressed in mammalian cells. The compound NNC 26-9100 showed a K-i of 6 nM at SST4 and more than 100 fold selectivity for SST4 over SST1, SST2, SST3, or SST5. Competition binding studies and Scatchard analysis of the interaction by NNC 26-9100 with SST showed specificity at SST4. Furthermore, NNC 26-9100 was highly selective for SST4 over a variety of other G protein-coupled receptors, having affinities for M-1 muscarinic acetylcholin and D-3 dopamine receptors of around 500 and 1000 nM, respectively. Finally, NNC 26-9100 was found to fully inhibit forskolin-induced accumulation of adenosine 3',5'-cyclic monophosphate in baby hamster kidney cells, expressing the human SST4 receptor with an EC50 of 2 nM.