对生长抑素受体亚型2具有选择性的强效拟肽的合成及生物活性
Synthesis and biological activities of potent peptidomimetics selective for somatostatin receptor subtype 2.
作者信息
Yang L, Berk S C, Rohrer S P, Mosley R T, Guo L, Underwood D J, Arison B H, Birzin E T, Hayes E C, Mitra S W, Parmar R M, Cheng K, Wu T J, Butler B S, Foor F, Pasternak A, Pan Y, Silva M, Freidinger R M, Smith R G, Chapman K, Schaeffer J M, Patchett A A
机构信息
Department of Medicinal Chemistry, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065, USA.
出版信息
Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10836-41. doi: 10.1073/pnas.95.18.10836.
A series of nonpeptide somatostatin agonists which bind selectively and with high affinity to somatostatin receptor subtype 2 (sst2) have been synthesized. One of these compounds, L-054,522, binds to human sst2 with an apparent dissociation constant of 0.01 nM and at least 3,000-fold selectivity when evaluated against the other somatostatin receptors. L-054,522 is a full agonist based on its inhibition of forskolin-stimulated adenylate cyclase activity in Chinese hamster ovary-K1 cells stably expressing sst2. L-054,522 has a potent inhibitory effect on growth hormone release from rat primary pituitary cells and glucagon release from isolated mouse pancreatic islets. Intravenous infusion of L-054,522 to rats at 50 microgram/kg per hr causes a rapid and sustained reduction in growth hormone to basal levels. The high potency and selectivity of L-054, 522 for sst2 will make it a useful tool to further characterize the physiological functions of this receptor subtype.
一系列非肽类生长抑素激动剂已被合成出来，它们能选择性地、高亲和力地与生长抑素受体亚型2（sst2）结合。其中一种化合物L-054,522，与人类sst2结合的表观解离常数为0.01 nM，在与其他生长抑素受体进行评估时，具有至少3000倍的选择性。基于其对稳定表达sst2的中国仓鼠卵巢-K1细胞中福斯克林刺激的腺苷酸环化酶活性的抑制作用，L-054,522是一种完全激动剂。L-054,522对大鼠原代垂体细胞的生长激素释放和分离的小鼠胰岛的胰高血糖素释放具有强效抑制作用。以每小时50微克/千克的剂量向大鼠静脉输注L-054,522会导致生长激素迅速且持续降低至基础水平。L-054,522对sst2的高效力和选择性将使其成为进一步表征该受体亚型生理功能的有用工具。
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