1,5-benzodiazepine tricyclic derivatives exerting anti-inflammatory effects in mice by inhibiting interleukin-6 and prostaglandin E2 production
1,5-benzodiazepine tricyclic derivatives exerting anti-inflammatory effects in mice by inhibiting interleukin-6 and prostaglandin E2 production
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DOI：
10.1006/phrs.2001.0800
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发表时间：
2001-05-01
影响因子：
9.3
通讯作者：
Roma, G
中科院分区：
文献类型：
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作者：
Fruscella, P;Sottocorno, M;Roma, G
1，4-和1，5-苯二氮卓类(BDZ)是常用的抗焦虑和抗惊厥药物。已有研究表明，它们影响某些免疫细胞特性，如促炎细胞因子的产生，尤其是通过刺激外周BDZ受体。一类新的[1，2，4]三唑并[4，3-a][1，5]苯并二氮杂衍生物(化合物IV)的出现促使我们更详细地研究了三个选定的化合物IV(N，N-dimethyl-1-phenyl-4H-[1，2，4]triazolo[4，3-a][1，5]benzodiazepin-5-amine；N，N-二丁基-4H-[1，2，4]三唑并[4，3-a][1，5]苯并二氮杂-5-胺；1-甲基-N，N-dimethyl-4H-[1，2，4]triazolo[4，3-a][1，5]benzodiazepin-5-amine)和一种结构相关的化合物(1-phenyl-4H-[1，2，4]triazolo[4，3-a][1，5]benzodiazepin-5(6H)-one).这些BDZ衍生物已经失去了与中枢和外周BDZ受体的亲和力。采用小鼠气囊局部炎症模型研究了这些化合物对白细胞体内迁移的影响。化合物A和B从50 mg kg(-1)剂量开始呈剂量依赖性地抑制角叉菜胶诱导的白细胞募集，而化合物C仅在较高剂量100 mg kg(-1)时有效。化合物D在所考虑的任何剂量下都没有发挥这种作用。化合物A、B和C对白细胞募集的影响与显著抑制渗出液中白介素6和前列腺素E-2的产生相平行，类似于消炎痛，并且通过部分降低血管通透性，这些特征可能与设计和开发4H-[I，2，4]三唑并[4，3-a][1.5]苯二氮卓-5-胺类化合物中的创新抗炎分子有关。(C)2001年学术出版社。
The 1,4- and the 1,5-benzodiazepines (BDZ) are commonly used as anxiolytic and anticonvulsive drugs. It has been suggested that they influence, particularly through stimulation of peripheral BDZ receptors, some immune cell properties such as pro-inflammatory cytokine production. The availability of a new class of [1,2,4]triazolo[4,3-a] [1,5]benzodiazepine derivatives (compounds IV), endowed with anti-inflammatory and/or analgesic properties but no antipentylenetetrazole activity, prompted us to investigate in more detail the anti-inflammatory properties of three selected compounds IV (N,N-dimethyl-1-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amine; N,N-dibutyl-4H-[1,2,4]triazolo[4,3-a] [1,5]benzodiazepin-5-amine; 1-methyl-N,N-dimethyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amine) and one structurally related compound (1-phenyl-4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5(6H)-one). These BDZ derivatives have lost their affinity for the central and peripheral BDZ receptors. The in vivo effect on leukocyte migration of these compounds was investigated by using the mouse air-pouch model of local inflammation. Compounds A and B, significantly inhibited the carrageenan-induced leukocyte recruitment in a dose-dependent manner starting from the dose of 50 mg kg(-1), whereas compound C was effective only at the higher dose of 100 mg kg(-1). Compound D did not exert such effects at any of the doses considered. The effect of compounds A, B and C on leukocyte recruitment was paralleled by a significant inhibition of interleukin-6 and prostaglandin E-2 production in the exudate, similarly to indomethacin, and by a partial reduction of vascular permeability, These features may be relevant for the design and development of innovative anti-inflammatory molecules among the 4H-[I,2,4]triazolo[4,3-a] [1.5]benzodiazepin-5-amine derivatives. (C) 2001 Academic Press.