Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists
Molecular mechanisms of glucocorticoid action and selective glucocorticoid receptor agonists
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DOI：
10.1016/j.mce.2007.05.019
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发表时间：
2007-09-15
影响因子：
4.1
通讯作者：
Buttgereit, Frank
中科院分区：
文献类型：
--
作者：
Stahn, Cindy;Loewenberg, Mark;Buttgereit, Frank
糖皮质激素（GC）是治疗风湿性和其他炎症性疾病最常用的抗炎和免疫抑制药物。它们的治疗作用被认为是由四种不同的作用机制介导的：由胞质糖皮质激素受体（cGCR）引起的经典基因组作用机制;也由cGCR引发的继发性非基因组效应;膜结合糖皮质激素受体（mGCR）介导的非基因组效应;与细胞膜相互作用引起的非特异性非基因组效应。GC作用的经典基因组机制可以分为两个过程：“反式阻遏”，其负责大量所需的抗炎和免疫调节作用，和“反式激活”，其与频繁发生的副作用以及一些免疫抑制活性相关[Ehrchen，J.，斯坦穆勒湖，Barczyk，K.，Tenbrock，K.，Nacken，W.，Eisenacher，M.，北胡斯大学，索尔格角，Sunderkotter，C.，Roth，J.，2007.糖皮质激素诱导人单核细胞特异性激活的抗炎亚型分化。Blood 109，1265-1274]。尽管人们为减少糖皮质激素的不良反应做了大量的努力，但对传统糖皮质激素的改进已接近极限。因此，传统的“老药”的新变化正在测试中，硝基类固醇和长循环脂质体糖皮质激素确实显示出有希望的结果。然而，问题的关键应该是设计质量上的新药，如选择性糖皮质激素受体激动剂（SEGRA）。这些创新的甾体或非甾体分子诱导反式阻遏，而反式激活过程受影响较小。关于两种不同GCR配体A276575和ZK 216348的首次报道显示了有希望的结果。在这里，我们回顾了糖皮质激素作用的上述机制，并特别注意优化糖皮质激素和SEGRA的发展。(c)2007爱思唯尔爱尔兰有限公司保留所有权利。
Glucocorticoids (GC) are the most common used anti-inflammatory and immunosuppressive drugs in the treatment of rheumatic and other inflammatory diseases. Their therapeutic effects are considered to be mediated by four different mechanisms of action: the classical genomic mechanism of action caused by the cytosolic glucocorticoid receptor (cGCR); secondary non-genomic effects which are also initiated by the cGCR; membrane-bound glucocorticoid receptor (mGCR)-mediated non-genomic effects; non-specific, non-genomic effects caused by interactions with cellular membranes. The classical, genomic mechanism of GC-action can be divided into two processes: "transrepression", which is responsible for a large number of desirable anti-inflammatory and immunomodulating effects, and "transactivation" which is associated with frequently occurring side effects as well as with some immunosuppressive activities [Ehrchen, J., Steinmuller, L., Barczyk, K., Tenbrock, K., Nacken, W., Eisenacher, M., Nordhues, U., Sorg, C., Sunderkotter, C., Roth, J., 2007. Glucocorticoids induce differentiation of a specifically activated, anti-inflammatory subtype of human monocytes. Blood 109, 1265-1274]. Great efforts have been made to diminish glucocorticoid-induced adverse effects, but the improvement of conventional glucocorticoids has almost reached its limits. As a consequence, new variations of the conventional "good old drugs" are being tested and nitro-steroids and long circulating liposomal glucocorticoids indeed show promising results. Nevertheless, crux of the matter should be the design of qualitatively new drugs, such as selective glucocorticoid receptor agonists (SEGRAs). These innovative steroidal or non-steroidal molecules induce transrepression, while transactivation processes are less affected. First reports on two different GCR ligands, A276575 and ZK216348, show promising results. Here, we review the above-mentioned mechanisms of glucocorticoid action and give particular attention to the development of optimized glucocorticoids and SEGRAs. (c) 2007 Elsevier Ireland Ltd. All rights reserved.