Contractile activities of structural analogs of leukotrienes C and D: role of the polar substituents.
Contractile activities of structural analogs of leukotrienes C and D: role of the polar substituents.
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白三烯 C 和 D 结构类似物的收缩活性：极性取代基的作用。
DOI：
10.1073/pnas.78.7.4579
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发表时间：
1981
影响因子：
11.1
通讯作者：
Corey,EJ
中科院分区：
文献类型：
--
作者：
Lewis,RA;Drazen,JM;Austen,KF;Toda,M;Brion,F;Marfat,A;Corey,EJ
本文对过敏性反应慢反应物质（sr - a）中白三烯组分的23个结构类似物进行了系统修饰，对其在豚鼠肺实质条和回肠上的收缩活性进行了测试。通过结构修饰，可以评估SRS-A白三烯C-1至C-6区的四个极性单元对平滑肌痉挛活性的单独贡献。s链肽的游离nh2末端氨基是充分发挥活性所必需的，其缺失或取代使活性降低了一个以上但不到两个数量级。游离甘氨酸羧基也明显具有类似的重要性。相反，C-1的游离类二十烷羧基对于气道和回肠的充分活性是不需要的。一个可用的5-去氧基类似物的不活性表明了C-5羟基的作用。亲核的二价硫对白三烯D （LTD）的活性并不重要，因为一种亚砜具有实质性的作用。由于C-5或C-6位置的外端比LTD活性低两个数量级以上，LTD的类二十烷和肽段之间的构象关系相当重要。一些证据表明，C20链和肽单元的相对几何排列对活性很重要，这与LTD真正受体的存在是一致的。
Twenty-three structural analogs of the leukotriene components of slow reacting substance of anaphylaxis (SRS-A), in which the polar regions of the leukotriene were systematically modified, were tested for their contractile activities on guinea pig pulmonary parenchymal strips and guinea pig ileum. The structural modifications allowed evaluation of the separate contributions of the four polar units in the C-1 to C-6 region of the SRS-A leukotrienes to smooth muscle spasmogenic activity. The free NH2-terminal amino group of the S-linked peptide was necessary for full activity, and its deletion or substitution reduced activity by more than one but less than two orders of magnitude. A similar level of importance was apparent for the free glycine carboxyl group. In contrast, a free eicosanoid carboxyl at C-1 is not required for full activity on the airway and for substantial activity on the ileum. A role for the C-5 hydroxyl is indicated by the inactivity of the one available 5-desoxy analog. Nucleophilic, divalent sulfur is not critical to leukotriene D (LTD) activity, in that one sulfoxide had substantial function. The conformational relationship between the eicosanoid and peptide moieties of LTD is of considerable importance in that epimers at the C-5 or C-6 position were less active than LTD by more than two orders of magnitude. Several lines of evidence suggest that the relative geometrical arrangement of the C20 chain and the peptide unit is important to activity, consistent with the existence of a true receptor for LTD.