Benzodiazepine gastrin and brain cholecystokinin receptor ligands: L-365,260.
Benzodiazepine gastrin and brain cholecystokinin receptor ligands: L-365,260.
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苯二氮卓类胃泌素和脑胆囊收缩素受体配体：L-365,260。
DOI：
10.1021/jm00121a004
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发表时间：
1989
影响因子：
7.3
通讯作者：
R. Freidinger
中科院分区：
文献类型：
--
作者：
Mark G. Bock;R. M. Dipardo;B. E. Evans;K. Rittle;W. L. Whitter;Daniel F. Veber;P. Anderson;R. Freidinger
还发现了获得类似选择性配体的第二种方法。将5（9）的NI-甲基衍生物以及更有效的12拆分成它们的光学对映体提供了突破。在这两种情况下，3S构型的对映体（10和13）对CCK-A受体具有选择性，而镜像3R构型的对映体（11和14）对CCK-B和胃泌素受体具有选择性。相反，重要的是要注意，相关的3-氨基苯并二氮杂对映体2和3对CCK-A受体都具有高度选择性。因此，脲对映异构体的相反选择性是3位立体化学和苯并二氮杂卓与芳基取代基之间的连接基团的性质的结果。这种立体选择性是否延伸到具有较大N1取代基如8的脲正在研究中。值得注意的是，这里报道的受体配体不区分中枢CCK-B和外周胃泌素受体。能够区分这些受体的配体将是额外的有价值的药理学工具，但这类试剂仍有待去乙酰化。我们也在探索CCK-A和CCK-B选择性的三维结构基础。在这些研究中开发的主要感兴趣的化合物是14（L-365，260），一种有效的和选择性的CCK-B和胃泌素受体配体。在另一份报告中，14显示与这些受体竞争性相互作用，并在各种动物模型中口服有效地作为胃泌素刺激的酸分泌的拮抗剂。本研究中公开的化合物构成了成功操纵苯并二氮杂环庚三烯核以产生对给定肽受体有效的非肽配体的另一个实例。这些苯二氮卓类药物与胃泌素和CCK-B受体结合方式的机制细微差别仍不清楚，苯二氮卓类药物通常对看似不同的受体类型具有亲和力的原因也不清楚。一种可能的解释可能与这些受体的个体发育、它们随后的结构关系以及它们与鸟嘌呤核苷酸结合蛋白的明显共同复合有关。化合物2和3（表I）是通过酰化1，3-二氢-3-氨基-1甲基-2H-1，4-苯并二氮杂-2-酮的相应对映体制备的（分别为15和16）与4-氯苯甲酸反应。11母体苯并二氮杂卓15和16根据公开的方法15、16合成，并通过结晶拆分。
A second approach to similarly selective ligands has also been discovered. The resolution of the Nl-methyl de-rivative of 5 (9) as well as the more potent 12 into their optical antipodes afforded the breakthrough. In both in-stances, the enantiomers of 3S configuration (10 and 13) show selectivity for the CCK-A receptor, whereas the mirror image 3R isomers (11 and 14) are selective for the CCK-B and gastrinreceptors. In contrast, it is important to note that related 3-amidobenzodiazepine enantiomers 2 and 3 are both highly selective for the CCK-A receptor. The opposing selectivities for the urea enantiomers are, therefore, a consequence of both the 3-position stereo-chemistry and the nature of the linking group between benzodiazepine and aryl substituent. Whether or not this stereoselectivity extendsto ureas with larger Nl sub-stituents such as 8 is under investigation. It is noteworthy that the receptor ligands reported here do not distinguish between central CCK-B and peripheral gastrin receptors. Ligands which could discriminate be-tween these receptors would be additional valuable pharmacological tools, but such agents remain to be de-veloped. We are also exploring the 3-dimensional struc-tural basis for the CCK-A and CCK-B selectivity. The compound of principal interest developed in these studies is 14 (L-365,260), a potent and selective CCK-B and gastrin receptor ligand. In a separate report, 14 is shown to interact competitively with these receptors and to be orally effective as an antagonist of gastrin-stimulated acid secretion in various animal models. 13 The compounds disclosed in this study constitute an-other example of the successful manipulation of the benzodiazepine nucleus to produce effectivenonpeptidal lig-ands for a given peptide receptor. The mechanistic nuances of the mode ofbinding of these benzodiazepines to the gastrin and CCK-B receptors remain unclear, as do the reasons why benzodiazepines, in general, have affinity for seemingly disparate receptor types. One possible ex-planation may reside with the ontogeny of these receptors, their consequent structural relationships, and their ap-parent common complexation to guanine nucleotide binding proteins. 14 Whatever the reason, our results support the hypothesis that the benzodiazepine core structure is amenable to the design of ligands for a variety of peptidereceptors, an effort which is continuing in these laboratories.Compounds 2 and 3 (Table I) were prepared by acylating the corresponding enantiomers ofl, 3-dihydro-3-amino-lmethyl-2H-l, 4-benzodiazepin-2-one (15 and 16, respec-tively) with 4-chlorobenzoic acid. 11 The parent benzodiazepines 15 and 16 were synthesized according to pub-lished methods15, 16 and resolved via the crystallization