Congener derivatives and conjugates of histamine: synthesis and tissue and receptor selectivity of the derivatives.
Congener derivatives and conjugates of histamine: synthesis and tissue and receptor selectivity of the derivatives.
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组胺的同源衍生物和缀合物：衍生物的合成以及组织和受体选择性。
DOI：
10.1021/jm00394a031
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发表时间：
1987
影响因子：
7.3
通讯作者：
Goodman,M
中科院分区：
文献类型：
--
作者：
Khan,MM;Melmon,KL;Marr-Leisy,D;Verlander,MS;Egli,M;Lok,S;Goodman,M
合成了一系列19种组胺的同源衍生物和缀合物，并进行了测试，以确定配体是否会改变各种组织中的常规组胺活性。衍生物，其中含有支链或非支链的脂肪族基团，芳香族酰胺基团，或二肽，表现出的亲和力组胺1型和/或2型受体是广泛不同的祖。中间链长为4个亚甲基的组胺的对三氟甲基衍生物（化合物13）是最有效的淋巴细胞H2受体激动剂，但对豚鼠心肌H2受体无活性。从该化合物中缺失单个亚甲基链（化合物12）导致其对淋巴细胞的H2活性和对主动脉的H1活性的完全丧失。化合物12成为淋巴细胞H：受体上的唯一Ht激动剂。二肽缀合物（化合物17）和脂肪族同源物衍生物（化合物18）（均具有四个亚甲基）保留了对豚鼠心肌H2受体的一些活性，但失去了它们对淋巴细胞H2受体的活性。因此，组胺可以在离咪唑部分一定距离的位点上被修饰，从而产生组织选择性组胺受体激动剂，如果组胺可以被衍生化，使其作用具有组织特异性和效应特异性，则衍生物将有助于探测受体微环境和受体本身的结构。如果在体内保持选择性作用，则衍生物可用于探索其免疫心血管调节作用，以期将其开发为治疗剂。我们先前已经报道了两个平行系列的β-肾上腺素能激动剂衍生物和两个β-受体拮抗剂的作用。在每个系列中，合成利用分子的胺末端，即使该部分不被认为负责受体的识别。这些衍生物的作用包括每个系列中效力和作用以及组织特异性的改变。1-8最引人注目的是，一般来说，激动剂和拮抗剂的类似衍生物具有类似的药理作用。也就是说，最有效或最有选择性的药物是每个系列的密切相关的衍生物。1-8由于衍生化过程没有操纵前体药物的受体识别部分（咪唑基团），我们推断配体连接到受体的一些微环境。如果是这样的话，组胺可以通过类似的衍生作用而具有效应特异性。我们利用组胺侧链末端的氨基，合成了第三系列的衍生物。本文介绍了我们的新组胺衍生物的合成，并总结了其比较药理学。
A series of 19 congener derivatives and conjugates of histamine was synthesized and tested to determine whether the ligands would alter the conventional histamine activity in various tissues. The derivatives, which contained either branched or unbranched aliphatic groups, aromatic amide groups, or dipeptides, exhibited affinities for histamine type 1 and/or type 2 receptors that were widely different from the progenitor. The p-trifluoromethyl derivative of histamine with an intermediate chain length of four methylenes (compound 13) was the most potent lymphocytes H2 receptor agonist but was inactive on guinea pig myocardium H2 receptors. The deletion of a single methylene chain (compound 12) from this compound resulted in total loss of its H2 activity on lymphocytes and its Hj activity on aorta. Compound 12 became an exclusive Ht agonist on lymphocytes H: receptors. The dipeptide conjugate (compound 17) and the aliphatic congener derivative (compound 18), both with four methylenes, retained some of the activity on guinea pig myocardium H2 receptors, but lost their activity on lymphocytes H2 receptors. Therefore, histamine can be modified at sites that are at a distance from the imidazole moiety, resulting in tissue selective histamine receptor agonists.If histaminecould be derivatized so that its effects be-came tissue and effect specific, the derivatives would be useful in probing the structure of the receptor microenvironment and of the receptor itself. If the selective effects were maintained in vivo, the derivatives could be used to explore their immune cardiovascular modulatory roles with a view toward developing them as therapeutic agents. We have previously reported the effects of two parallel series of derivatives of a ß-adrenergic agonist and two^-antagonists. 1" 8 In each series, the synthesis utilized the amine end of the molecule even though this moiety was not considered responsible for recognition of the receptor. The effects of these derivatives included alterations of potency and effect and tissue specificity in each series. 1-8 What was most striking was that generally the analogous derivatives of the agonist and antagonists had an analogous skew of their pharmacologic effects. That is, the most potent or selective drugs were the closely related deriva-tives of each series. 1-8 Since the derivatization process did not manipulate the receptor recognition moiety (imidazole group) of the progenitor drugs, we reasoned that the lig-ands attached to some microenvironment of the ß receptor. If such were the case, histamine might be made effect specific by similar derivatization. We took advantage of the side-chain terminal amino group on histamine to make a third series ofderivatives. This paper describes the synthesis and summarizes the comparative pharmacology of our new histamine deriva-