Functional reversal of (−)‐Stepholidine analogues by replacement of benzazepine substructure using the ring‐expansion strategy

(−)‐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 .