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

Abstract

(-)-Stepholidine (l-SPD) is an active ingredient of the Chinese herb Stephania and naturally occurring tetrahydroprotoberberine (THPB) alkaloid with mixed dopamine receptor D₁ (D1R) agonistic and dopamine receptor D₂ (D2R) 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 l-SPD. Initial pharmacological assays demonstrated that a benzazepine replacement was associated with significant increase of selectivity and functional reversal at D1R. Compound-(-)-15e (K_i = 5.32±0.01 nM) is more potent than l-SPD (Ki = 13 nM) and was identified as a selective D1R antagonist (IC₅₀ = 0.14 μM). Moreover, molecular modeling suggested that (-)-15e might exert its D1R antagonistic activities through interacting with the transmembrane helix 7 (TM7) of D1R.

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A series of novel ring-expanded analogues of (−)-Stepholidine (l-SPD) were designed, synthesized and bioassayed as potent ligands at D1R. Compound-(-)-15e (Ki = 5.32±0.01 nM) is more potent than l-SPD (Ki = 13 nM) and was identified as a selective D1R antagonist (IC₅₀ = 0.14 μM). This structural modification was associated significant increase of selectivity and functional reversal at D1R in comparison to (-)-l-SPD with dual D1R agonistic and D2R antagnositic activities.

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