Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists

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  • Mao, Q
    • Other Affiliation: Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Jiangsu, Suzhou, China
  • Zhang, B
    • Other Affiliation: iHuman Institute, ShanghaiTech University, Shanghai, China
  • Tian, S
    • Other Affiliation: Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Jiangsu, Suzhou, China
  • Qin, W
    • Other Affiliation: Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Jiangsu, Suzhou, China
  • Chen, J
    • Other Affiliation: Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Jiangsu, Suzhou, China
  • Huang, X.-P
    • School of Medicine, Department of Pharmacology
  • Xin, Y
    • Other Affiliation: iHuman Institute, ShanghaiTech University, Shanghai, China
  • Yang, H
  • Zhen, X.-C
    • Other Affiliation: Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Jiangsu, Suzhou, China
  • Shui, W
    • Other Affiliation: iHuman Institute, ShanghaiTech University, Shanghai, China
  • Ye, N
    • Other Affiliation: Jiangsu Key Laboratory of Neuropsychiatric Diseases and College of Pharmaceutical Sciences, Soochow University, Jiangsu, Suzhou, China
Abstract
  • The concept of subtype selectivity and functional bias has recently reshaped current GPCR drug discovery for G protein-coupled receptors. A series of new N-H aporphines with A-ring modifications have been synthesized, and their efficacy on 5-HT2 receptor activation was evaluated. SAR analysis led to the discovery of several more potent and selective 5-HT2C receptor agonists (e.g., 11b and 11f) with low nanomolar activity. Molecular docking analysis of this series of aporphines was in accordance with our SAR results. The functional selectivity of specific compounds was tested via both Gq-mediated calcium flux and β-arrestin recruitment assays, which revealed that these compounds exhibited no β-arrestin recruitment activity. Further ADMET study combined with behavioral assessment using a methamphetamine-induced hyperactivity model identified compound 11b and 11f possessing promising drug-like profiles and having antipsychotic potential. These agonists with an exclusive bias toward Gq signaling may serve as valuable pharmacological probes to facilitate the elucidation of therapeutically relevant 5-HT2C signaling pathways and the development of alternative antipsychotic medications.
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Resource type
  • Article
Rights statement
  • In Copyright
Journal title
  • Bioorganic Chemistry
Journal volume
  • 123
Language
  • English
Version
  • Postprint
Funder
  • National Key Research and Development Program of China, NKRDPC: 2018YFA0507004, 2021YFE0206000
  • Priority Academic Program Development of Jiangsu Higher Education Institutions, PAPD
  • University of North Carolina, UNC
  • National Institute of Mental Health, NIMH
  • Suzhou Municipal Science and Technology Bureau: SYS2020092
  • National Natural Science Foundation of China, NSFC: 22177086, 31971362, 81703330
  • BM2013003
  • Soochow University
ISSN
  • 0045-2068
Publisher
  • Academic Press Inc.

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