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首页> 外文期刊>Journal of Medicinal Chemistry >New serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptor antagonists: synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo and heterocycloalkanones.
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New serotonin 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptor antagonists: synthesis, pharmacology, 3D-QSAR, and molecular modeling of (aminoalkyl)benzo and heterocycloalkanones.

机译：新的5-羟色胺5-HT（2A），5-HT（2B）和5-HT（2C）受体拮抗剂：合成，药理学，3D-QSAR和（氨基烷基）苯并和杂环链烷酮的分子模型。

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A series of 52 conformationally constrained butyrophenones have been synthesized and pharmacologically tested as antagonists at 5-HT(2A), 5-HT(2B), and 5-HT(2C) serotonin receptors, useful for dissecting the role of each 5-HT(2) subtype in pathophysiology. These compounds were also a consistent set for the identification of structural features relevant to receptor recognition and subtype discrimination. Six compounds were found highly active (pK(i) > 8.76) and selective at the 5-HT(2A) receptor vs 5-HT(2B) and/or 5-HT(2C) receptors. Piperidine fragments confer high affinity at the 5-HT(2A) receptor subtype, with benzofuranone- and thiotetralonepiperidine as the most selective derivatives over 5-HT(2C) and 5-HT(2B) receptors, respectively; K(i) (2A/2C) and/or K(B) (2A/2B) ratios greater than 100 were obtained. Compounds showing a more pronounced selectivity at 5-HT(2A)/5-HT(2C) than at 5-HT(2A)/5-HT(2B) bear 6-fluorobenzisoxazolyl- and p-fluorobenzoylpiperidine moieties containing one methylene bridging the basic piperidine to the alkanone moiety. An ethylene bridge between the alkanone and the amino moieties led to ligands with higher affinities for the 5-HT(2B) receptor. Significant selectivity at the 5-HT(2B) receptor vs 5-HT(2C) was observed with 1-1[(1-oxo-1,2,3,4-tetrahydro-3-naphthyl)methyl]-4-[3-(p-fluorobenzoyl)propyl]piperazine (more than 100-fold higher). Although piperidine fragments also confer higher affinity at 5-HT(2C) receptors, only piperazine-containing ligands were selective over 5-HT(2A). Moderate selectivity was observed at 5-HT(2C) vs 5-HT(2B) (10-fold) with some compounds bearing a 4-[3-(6-fluorobenzisoxazolyl)]piperidine moiety in its structure. Molecular determinants for antagonists acting at 5-HT(2A) receptors were identified by 3D-QSAR (GRID-GOLPE) studies. Docking simulations at 5-HT(2A) and 5-HT(2C) receptors suggest a binding site for the studied type of antagonists (between transmembrane helices 2, 3, and 7) different to that of the natural agonist serotonin (between 3, 5, and 6).
机译：已经合成了一系列52种受构象约束的丁苯酮，并在药理学上测试了它们在5-HT（2A），5-HT（2B）和5-HT（2C）血清素受体上的拮抗作用，可用于剖析各5-HT的作用（2）病理生理亚型。这些化合物也是用于鉴定与受体识别和亚型识别有关的结构特征的一致组。发现有六个化合物具有高活性（pK（i）> 8.76），并且对5-HT（2A）受体相对于5-HT（2B）和/或5-HT（2C）受体具有选择性。哌啶片段在5-HT（2A）受体亚型上具有较高的亲和力，苯并呋喃酮-和硫代四氢萘哌啶分别是对5-HT（2C）和5-HT（2B）受体的选择性最高的衍生物;获得的K（i）（2A / 2C）和/或K（B）（2A / 2B）比率大于100。在5-HT（2A）/ 5-HT（2C）处比在5-HT（2A）/ 5-HT（2B）处显示出更明显选择性的化合物带有6-氟苯并恶唑基和对氟苯甲酰基哌啶基团，其中一个亚甲基桥接碱性哌啶至烷酮部分。烷酮和氨基部分之间的乙烯桥导致对5-HT（2B）受体具有更高亲和力的配体。与1-1 [（1-oxo-1,2,3,4-tetrahydro-3-naphthyl）methyl] -4-[[1-oxo-1,2,3,4-tetrahydro-3-萘基）甲基]观察到在5-HT（2B）受体对5-HT（2C）的显着选择性。 3-（对氟苯甲酰基）丙基]哌嗪（高100倍以上）。虽然哌啶片段还赋予5-HT（2C）受体更高的亲和力，但只有含哌嗪的配体对5-HT（2A）具有选择性。在5-HT（2C）与5-HT（2B）处观察到中等选择性（10倍），其中一些化合物的结构中带有4- [3-（6-氟苯并恶唑基）]哌啶部分。通过3D-QSAR（GRID-GOLPE）研究确定了作用于5-HT（2A）受体的拮抗剂的分子决定簇。在5-HT（2A）和5-HT（2C）受体上的对接模拟表明，所研究类型的拮抗剂（跨膜螺旋2、3和7之间）的结合位点与天然激动剂5-羟色胺（在3之间， 5和6）。

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