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

Chem Biol Drug Des. 2016 Oct;88(4):599-607. doi: 10.1111/cbdd.12796. Epub 2016 Jun 24.


(-)-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 .

Keywords: Receptor and ligands (agonist/antagonist); dopamine D1 receptor; selective D1R antagonists.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Benzazepines / chemical synthesis*
  • Benzazepines / chemistry
  • Benzazepines / pharmacology
  • Berberine / analogs & derivatives*
  • Berberine / chemical synthesis
  • Berberine / chemistry
  • Berberine / pharmacology
  • Binding Sites
  • Biological Assay
  • Dopamine D2 Receptor Antagonists / chemical synthesis
  • Dopamine D2 Receptor Antagonists / chemistry
  • Dopamine D2 Receptor Antagonists / pharmacology
  • Humans
  • Models, Molecular
  • Receptors, Dopamine D1* / antagonists & inhibitors
  • Receptors, Dopamine D2* / chemistry
  • Receptors, Dopamine D2* / drug effects


  • Benzazepines
  • Dopamine D2 Receptor Antagonists
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Berberine
  • stepholidine