The C3a receptor antagonist SB 290157 has agonist activity
The C3a receptor antagonist SB 290157 has agonist activity
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DOI：
10.1016/j.imlet.2005.03.003
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发表时间：
2005-09-15
影响因子：
4.4
通讯作者：
Therien, AG
中科院分区：
文献类型：
--
作者：
Mathieu, MC;Sawyer, N;Therien, AG
过敏毒素C3a是一种重要的免疫调节剂，在先天免疫和适应性免疫中具有许多不同的功能。基于对小鼠进行基因改造，使其前体C3或受体C3aR缺失的研究，许多这些作用被归因于C3a。然而，C3a的其他假定功能是基于最近描述的C3aR小分子配体SB 290157获得的结果。虽然这种化合物最初被描述为一种拮抗剂，并且在某些系统中似乎起着拮抗剂的作用，但它最近被证明具有不能用C3aR的简单拮抗剂来解释的作用。在目前的研究中，SB 290157被证明在多种细胞系统中对C3aR具有充分的激动剂活性，包括转染的RBL细胞中的钙动员试验，CHO-NFAT-bla-G α(16)细胞中的β -内酰胺酶试验和分化的U-937细胞中的酶释放试验。另一方面，该化合物在豚鼠血小板中缺乏激动剂活性，已知血小板表达C3aR的水平非常低。SB 290157对C3aR的激动作用与最近使用该分子获得的差异数据一致。这些结果提醒我们不要根据SB 290157获得的数据将C3a的新作用归因于C3a，并强调继续需要鉴定真正的小分子C3aR拮抗剂。(c) 2005 Elsevier B.V.版权所有
The anaphylatoxin C3a is an important immune regulator with a number of distinct functions in both innate and adaptive immunity. Many of these roles have been ascribed to C3a based on studies in mice genetically modified to lack its precursor, C3, or its receptor, C3aR. However, other presumed functions of C3a are based on results obtained with a recently described small molecule ligand of C3aR, SB 290157. Although this compound was originally described as an antagonist and appears to act as such in some systems, it has recently been shown to have effects that cannot be explained by simple antagonism of C3aR. In the cur-rent study, SB 290157 is shown to have full agonist activity on C3aR in a variety of cell systems, including a calcium mobilization assay in transfected RBL cells, a beta-lactamase assay in CHO-NFAT-bla-G alpha(16) cells and an enzyme-release assay in differentiated U-937 cells. On the other hand, the compound lacks agonist activity in guinea pig platelets, cells known to express C3aR at very low levels. SB 290157 agonism of C3aR is consistent with recent discrepant data obtained using this molecule. These results caution against attributing novel roles to C3a based on data obtained with SB 290157 and highlight a continuing need for the identification of true small molecule C3aR antagonists. (c) 2005 Elsevier B.V. All rights reserved.