构象受限的阿片样物质配体：Dmt-Aba和Dmt-Aia与Dmt-Tic支架的比较
Conformationally constrained opioid ligands: the Dmt-Aba and Dmt-Aia versus Dmt-Tic scaffold.
作者信息
Ballet Steven, Feytens Debby, Wachter Rien De, Vlaeminck Magali De, Marczak Ewa D, Salvadori Severo, Graaf Chris de, Rognan Didier, Negri Lucia, Lattanzi Roberta, Lazarus Lawrence H, Tourwé Dirk, Balboni Gianfranco
机构信息
Department of Organic Chemistry, Vrije Universiteit Brussel, Pleinlaan 2, B-1050 Brussels, Belgium.
出版信息
Bioorg Med Chem Lett. 2009 Jan 15;19(2):433-7. doi: 10.1016/j.bmcl.2008.11.051. Epub 2008 Nov 19.
Abstract
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 mu-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 peptidomimetic 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.
摘要
在阿片类药物Dmt-Tic-Gly-NH-Bn支架中，用4-氨基-1,2,4,5-四氢吲哚并[2,3-c]氮杂环庚-3-酮（Aia）和4-氨基-1,2,4,5-四氢-2-苯并氮杂环庚-3-酮（Aba）支架取代受限的苯丙氨酸类似物1,2,3,4-四氢异喹啉-3-羧酸（Tic），已导致发现新型强效μ-选择性激动剂（结构5和12）以及强效和选择性δ-阿片受体拮抗剂（结构9和15）。在研究的小肽模拟模板中，立体化学和N端N,N-二甲基化均被证明是影响阿片受体选择性和功能生物活性的关键因素。除了体外药理学评估外，还构建了Dmt-Tic和Dmt-Aba类似物的自动对接模型，以便对观察到的构效关系数据进行合理化分析。
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