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.
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.
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新型1,3,4,11b-四氢-1H-芴[9,1-cd]氮杂卓框架的合成、药理学评价和分子对接研究：D1受体选择性1-苯基苯并氮杂卓的刚性化和新5-苯并氮杂卓的发现
DOI：
10.1111/cbdd.13691
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发表时间：
2020
影响因子：
3
通讯作者：
Harding,WayneW
中科院分区：
文献类型：
--
作者：
Giri,Rajan;Alberts,Ian;Harding,WayneW
以1-苯基苯并氮杂卓为模板，通过直接芳基化反应合成了一种新型的1，3，4，11 b-四氢-1H-芴并[9，1-cd]氮杂卓骨架。对硬化化合物在一组血清素、多巴胺和肾上腺素能受体上的结合亲和力的评价表明，该支架出乎意料地对D1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受体的亲和力受到电子和疏水相互作用以及配体刚性增强的显著影响。分子对接研究表明，刚性化合物的D1受体亲和力降低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的氢键相互作用较弱。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的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-芴并[9，1-cd]氮杂卓）和12（6，7-二甲氧基-2-甲基-2，3，4，11b-四氢-1H-芴并[9，1-cd]氮杂卓）已被鉴定为结构新颖、高亲和力（Ki= 5 nM）、选择性5-HT 6受体配体。
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 D1and other dopamine receptors and is selective for the 5‐HT6receptor. The affinity of these systems at the 5‐HT6receptor is significantly influenced by electronic and hydrophobic interactions as well as the enhanced rigidity of the ligands. Molecular docking studies indicate that the reduced D1receptor 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‐HT6receptor affinity of the compounds. Compounds10(6,7‐dimethoxy‐2,3,4,11b‐tetrahydro‐1H‐fluoreno[9,1‐cd]azepine) and12(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‐HT6receptor ligands.