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Identification and synthesis of low-molecular weight cholecystokinin B receptor (CCKBR) agonists as mediators of long-term synaptic potentiation

  • Yanmei ZhangEmail author
  • Yican Wang
  • Yiping Guo
  • Jinxi Liao
  • Zhengchao Tu
  • Yongzhi Lu
  • Ke Ding
  • Micky D. Tortorella
  • Jufang HeEmail author
Original Research
  • 24 Downloads

Abstract

Recently, He et al. reported that CCKB receptors located in the neocortex of the brain when bound to their bound natural ligand, CCK peptides, enhance memory, bringing up the possibility that agonists targeting the CCKB receptor may act as therapeutic agents in diseases in which memory loss is marked as observed in dementia and Alzheimer’s. In this report, we describe the synthesis of novel low-molecular weight benzoamine CCKB receptor agonists. The compounds made in this series were determined to be mostly partial agonists, although some antagonists were identified, as well, capable of triggering calcium release in a cell line that overexpresses the CCKB receptor. Compound 35 demonstrated an EC50 of 0.15 µM in the cell-based assay, but more importantly, several of the compounds, including 35, demonstrated a physiological effect, inducing long-term potentiation in rat brains comparable to the CCK-8 peptide albeit at much higher concentrations. Based on these findings, benzoamines may be the basis for a new series of CCKB receptor agonists in drug-discovery efforts that seek to develop therapeutics to prevent memory loss.

Keywords

Cholecystokinin B receptor Agonist Synaptic potentiation Memory 

Notes

Acknowledgements

Thise research work was financially supported by the Guangzhou Science & Technology Project (2011Y2-00026 and 201508020131) to support GIBH Drug Discovery Pipeline Development (Y.Z.), the Guangdong Science & technology Project ((2014B050505016) (M.T.), (2013B050800009) (Y.Z.), and (2013B040200031) (Z.T.)), and CAS Key Technology Talent Program China (2013) (Z.T.).

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yanmei Zhang
    • 1
    Email author
  • Yican Wang
    • 1
  • Yiping Guo
    • 1
  • Jinxi Liao
    • 1
  • Zhengchao Tu
    • 1
  • Yongzhi Lu
    • 1
  • Ke Ding
    • 1
  • Micky D. Tortorella
    • 1
  • Jufang He
    • 2
    Email author
  1. 1.Drug Discovery Pipeline, Guangzhou Institutes of Biomedicine and HealthScience CityGuangzhouChina
  2. 2.Division of Life ScienceHong Kong University of Science and TechnologyHong Kong SARChina

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