Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold
Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold
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DOI：
10.1016/j.bmcl.2008.11.051
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发表时间：
2009-01-15
影响因子：
2.7
通讯作者：
Balboni, Gianfranco
中科院分区：
文献类型：
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作者：
Ballet, Steven;Feytens, Debby;Balboni, Gianfranco
用4-氨基-1，2，4，5-四氢-吲哚并[2，3-c]氮杂卓-3-酮（Aia）和4-氨基-1，2，4，5-四氢-2-苯并氮杂卓-3-酮（阿坝）支架导致了新的有效的l-选择性激动剂的发现（结构5和12）以及有效和选择性δ-阿片样物质受体拮抗剂（结构9和15）。在所研究的小肽模拟物模板中，立体化学和N-末端N，N-二甲基化被证明是阿片受体选择性和功能生物活性的关键因素。除了体外药理学评价外，还构建了Dmt-Tic和Dmt-Aba类似物的自动对接模型，以使观察到的结构活性数据合理化。(C)2008爱思唯尔有限公司保留所有权利。
Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent l-selective agonists (Structures 5 and 12) as well as potent and selective delta-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small pepti-domimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure activity data. (C) 2008 Elsevier Ltd. All rights reserved.