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Synthesis, pharmacological evaluations, and molecular docking studies on a new 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework: Rigidification of D1 receptor selective 1-phenylbenzazepines and discovery of a new 5-HT6 receptor scaffold.
Chemical Biology & Drug Design ( IF 3 ) Pub Date : 2020-04-11 , DOI: 10.1111/cbdd.13691
Rajan Giri 1, 2 , Ian Alberts 3 , Wayne W Harding 1, 2, 4
Affiliation  

The novel 1,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine framework, a structurally rigidified variant of the 1‐phenylbenzazepine template, was synthesized via direct arylation as a key reaction. Evaluation of the binding affinities of the rigidified compounds across a battery of serotonin, dopamine, and adrenergic receptors indicates that this scaffold unexpectedly has minimal affinity for D1 and other dopamine receptors and is selective for the 5‐HT6 receptor. The affinity of these systems at the 5‐HT6 receptor is significantly influenced by electronic and hydrophobic interactions as well as the enhanced rigidity of the ligands. Molecular docking studies indicate that the reduced D1 receptor affinity of the rigidified compounds may be due in part to weaker H‐bonding interactions between the oxygenated moieties on the compounds and specific receptor residues. Key receptor–ligand H‐bonding interactions, salt bridges, and π–π interactions appear to be responsible for the 5‐HT6 receptor affinity of the compounds. Compounds 10 (6,7‐dimethoxy‐2,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine) and 12 (6,7‐dimethoxy‐2‐methyl‐2,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine) have been identified as structurally novel, high affinity (Ki = 5 nM), selective 5‐HT6 receptor ligands.

中文翻译:

新的 1,3,4,11b-四氢-1H-芴[9,1-cd]氮杂框架的合成、药理学评价和分子对接研究:D1 受体选择性 1-苯基苯并氮杂的刚性化和新的 5- HT6 受体支架。

新型 1,3,4,11b-四氢-1 H-芴[9,1- cd ]氮杂骨架是 1-苯基苯并氮杂模板的结构刚性变体,是通过直接芳基化作为关键反应合成的。对一组 5-羟色胺、多巴胺和肾上腺素能受体的刚性化合物的结合亲和力的评估表明,该支架意外地对 D 1和其他多巴胺受体具有最小的亲和力,并且对 5-HT 6受体具有选择性。这些系统对 5-HT 6受体的亲和力受电子和疏水相互作用以及配体刚性增强的显着影响。分子对接研究表明,减少的 D 1硬化化合物的受体亲和力可能部分是由于化合物上的含氧部分与特定受体残基之间较弱的氢键相互作用。关键的受体-配体氢键相互作用、盐桥和 π-π 相互作用似乎是化合物对 5-HT 6受体亲和力的原因。化合物10 (6,7-二甲氧基-2,3,4,11b-四氢-1H-芴[9,1-cd]氮杂) 和12 (6,7-二甲氧基-2-甲基-2,3,4, 11b-四氢-1H-芴[9,1-cd]氮杂)已被鉴定为结构新颖、高亲和力(K i  = 5 nM)、选择性5-HT 6受体配体。
更新日期:2020-04-11
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