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 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 .