Structure activity relationships for bradykinin antagonists on the inhibition of cytokine release and the release of histamine

被引:12
作者
Reissmann, S [1 ]
Pineda, F
Vietinghoff, G
Werner, H
Gera, L
Stewart, JM
Paegelow, I
机构
[1] Univ Jena, Fac Biol, Inst Biochem & Biophys, D-07743 Jena, Germany
[2] Univ Rostock, Inst Expt & Clin Pharmacol & Toxicol, D-18057 Rostock, Germany
[3] Univ Colorado, Sch Med, Dept Biochem, Denver, CO 80262 USA
关键词
bradykinin receptor antagonists; inhibition of cytokine release; histamine release; mast cells; structure activity relationships; spleen mononuclear cells; tanned erythrocyte electrophoretic mobility (TEEM) test; QSAR;
D O I
10.1016/S0196-9781(00)00171-6
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Highly potent bradykinin antagonists were found to inhibit bradykinin-induced release of cytokines but to stimulate histamine release. Both actions show structural requirements completely different from those for bradykinin B-1 and B-2 receptors, indicating that the release of some cytokines from spleen mononuclear cells and of histamine from rat mast cells is not mediated by these receptors, Most potent bradykinin antagonists release histamine at lower concentrations than does bradykinin itself. Dimers of bradykinin antagonists are the most potent compounds for histamine release. in contrast to enhanced histamine release, potent inhibition of cytokine release enhances the applicability of these compounds as anti-inflammatory drugs. Many of the peptides designed for high B-2-receptor antagonism were found to be compared by their concentrations far more potent for inhibition of cytokine release than for smooth muscle contraction. Thus, for some antagonists inhibition of cytokine release was detected at concentrations as low as 10(-15) M. The rational design of peptide and nonpeptide bradykinin antagonists for therapeutic use requires not only knowledge about the potency but also knowledge about the structure-activity relationships of such important side effects as cytokine and histamine release. (C) 2000 Elsevier Science Inc. All rights reserved.
引用
收藏
页码:527 / 533
页数:7
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