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

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

Author information

1
Department of Medicinal Chemistry & Key Laboratory of Smart Drug Delivery, Ministry of Education & PLA, School of Pharmacy, Fudan University, Shanghai, China.
2
Jiangsu Key Laboratory of Translational Research and Therapy for Neuropsychiatricdisorders & Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China.
3
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.
4
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.

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 .

KEYWORDS:

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

PMID:
27232055
DOI:
10.1111/cbdd.12796
[Indexed for MEDLINE]

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