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Functional reversal of (−)‐Stepholidine analogues by replacement of benzazepine substructure using the ring‐expansion strategy
Author(s) -
Li Wei,
Zhang Li,
Xu Lili,
Yuan Congmin,
Du Peng,
Chen Jiaojiao,
Zhen Xuechu,
Fu Wei
Publication year - 2016
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.12796
Subject(s) - benzazepine , chemistry , dopamine , dopamine receptor d2 , dopamine receptor , stereochemistry , receptor , pharmacology , biology , biochemistry , endocrinology
(−)‐Stepholidine is an active ingredient of the Chinese herb Stephania and naturally occurring tetrahydroprotoberberine alkaloid with mixed dopamine receptor D 1 agonistic and dopamine receptor D 2 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 D 1 . Compound‐(−)‐ 15e ( K i = 5.32 ± 0.01 n m ) is more potent than (−)‐Stepholidine ( K i = 13 n m ) and was identified as a selective dopamine receptor D 1 antagonist ( IC 50 = 0.14 μ m ). Moreover, molecular modeling suggested that (−)‐ 15e might exert its dopamine receptor D 1 antagonistic activities through interacting with the transmembrane helix 7 of dopamine receptor D 1 .