Functional reversal of (−)‐Stepholidine analogues by replacement of benzazepine substructure using the ring‐expansion strategy
Functional reversal of (−)‐Stepholidine analogues by replacement of benzazepine substructure using the ring‐expansion strategy
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DOI：
10.1111/cbdd.12796
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发表时间：
2016-10
影响因子：
3
通讯作者：
Wei Li;Li Zhang;Lili Xu;C. Yuan;Peng Du;Jiaojiao Chen;Xuechu Zhen;Wei-Chang Fu
中科院分区：
文献类型：
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作者：
Wei Li;Li Zhang;Lili Xu;C. Yuan;Peng Du;Jiaojiao Chen;Xuechu Zhen;Wei-Chang Fu
（−）-千金藤定是中药千金藤属的活性成分，也是天然存在的四氢原小檗碱生物碱，具有多巴胺受体D1激动和多巴胺受体D2拮抗活性。本论文设计并合成了一系列六氢苯并[4，5]氮杂卓并[2，1-a]异喹啉类化合物作为（-）-千金藤啶的扩环类似物。初步的药理学试验表明，苯并氮卓类药物的替代与多巴胺受体D1的选择性和功能逆转的显着增加。化合物-（-）-15e（Ki = 5.32 ± 0.01 nm）比（-）-千金藤啶（Ki = 13 nm）更有效，被鉴定为选择性多巴胺受体D1拮抗剂（IC 50 = 0.14 μm）。此外，分子模拟表明，（−）-15e可能通过与多巴胺受体D1的跨膜螺旋7相互作用而发挥其多巴胺受体D1拮抗活性。
(−)‐Stepholidine is an active ingredient of the Chinese herb Stephania and naturally occurring tetrahydroprotoberberine alkaloid with mixed dopamine receptor D1 agonistic and dopamine receptor D2 antagonistic activities. In this work, a series of novel hexahydrobenzo[4,5]azepino [2,1‐a]isoquinolines were designed and synthesized as ring‐expanded analogues of (−)‐Stepholidine. Initial pharmacological assays demonstrated that a benzazepine replacement was associated with significant increase in selectivity and functional reversal at dopamine receptor D1. Compound‐(−)‐15e (Ki = 5.32 ± 0.01 nm) is more potent than (−)‐Stepholidine (Ki = 13 nm) and was identified as a selective dopamine receptor D1 antagonist (IC50 = 0.14 μm). Moreover, molecular modeling suggested that (−)‐15e might exert its dopamine receptor D1 antagonistic activities through interacting with the transmembrane helix 7 of dopamine receptor D1.