title: Functional reversal of (-)-Stepholidine analogues by replacement of benzazepine substructure using the ring-expansion strategy.
abstract: (-)-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 .
authors.affiliation: Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatricdisorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Congmin
authors.initials: C
authors.lastname: Yuan
authors.affiliation: Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai, China.
authors.forename: Peng
authors.initials: P
authors.lastname: Du
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatricdisorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
authors.forename: Jiaojiao
authors.initials: J
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatricdisorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China. Zhenxuechu@suda.edu.cn.
authors.forename: Xuechu
authors.initials: X
authors.lastname: Zhen
authors.affiliation: Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai, China. wfu@fudan.edu.cn.
authors.forename: Wei
authors.initials: W
authors.lastname: Fu
mesh_terms: D001552:Benzazepines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001599:Berberine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D001681:Biological Assay; D065127:Dopamine D2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors; D017448:Receptors, Dopamine D2 / Q000737:chemistry / Q000187:drug effects
chemical_list: D001552:Benzazepines; D065127:Dopamine D2 Receptor Antagonists; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D001599:Berberine; C010513:stepholidine
keywords: Receptor and ligands (agonist/antagonist); dopamine D1 receptor; selective D1R antagonists