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 +/- 0.01nm) is more potent than (-)-Stepholidine (K-i=13nm) and was identified as a selective dopamine receptor D-1 antagonist (IC50=0.14m). 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.