Design of donecopride, a dual serotonin subtype 4 receptor agonist/acetylcholinesterase inhibitor with potential interest for Alzheimer's disease treatment

Proc Natl Acad Sci U S A. 2014 Sep 9;111(36):E3825-30. doi: 10.1073/pnas.1410315111. Epub 2014 Aug 25.


RS67333 is a partial serotonin subtype 4 receptor (5-HT4R) agonist that has been widely studied for its procognitive effect. More recently, it has been shown that its ability to promote the nonamyloidogenic cleavage of the precursor of the neurotoxic amyloid-β peptide leads to the secretion of the neurotrophic protein sAPPα. This effect has generated great interest in RS67333 as a potential treatment for Alzheimer's disease (AD). We show herein that RS67333 is also a submicromolar acetylcholinesterase (AChE) inhibitor and therefore, could contribute, through this effect, to the restoration of the cholinergic neurotransmission that becomes altered in AD. We planned to pharmacomodulate RS67333 to enhance its AChE inhibitory activity to take advantage of this pleiotropic pharmacological profile in the design of a novel multitarget-directed ligand that is able to exert not only a symptomatic but also, a disease-modifying effect against AD. These efforts allowed us to select donecopride as a valuable dual (h)5-HT4R partial agonist (Ki = 10.4 nM; 48.3% of control agonist response)/(h)AChEI (IC50 = 16 nM) that further promotes sAPPα release (EC50 = 11.3 nM). Donecopride, as a druggable lead, was assessed for its in vivo procognitive effects (0.1, 0.3, 1, and 3 mg/kg) with an improvement of memory performances observed at 0.3 and 1 mg/kg on the object recognition test. On the basis of these in vitro and in vivo activities, donecopride seems to be a promising drug candidate for AD treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy*
  • Alzheimer Disease / physiopathology
  • Amyloid beta-Peptides / metabolism
  • Aniline Compounds / chemistry
  • Aniline Compounds / pharmacology
  • Aniline Compounds / therapeutic use
  • Animals
  • Brain / drug effects
  • Brain / metabolism
  • COS Cells
  • Chlorocebus aethiops
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology
  • Cholinesterase Inhibitors / therapeutic use*
  • Cognition / drug effects
  • Cyclosporine / pharmacology
  • Drug Design*
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels / metabolism
  • Kinetics
  • Ligands
  • Mice
  • Permeability / drug effects
  • Piperidines / chemistry
  • Piperidines / pharmacology
  • Piperidines / therapeutic use*
  • Receptors, Serotonin, 5-HT4 / metabolism
  • Receptors, Serotonin, 5-HT4 / therapeutic use
  • Rhodamine 123 / metabolism
  • Serotonin 5-HT4 Receptor Agonists / chemistry
  • Serotonin 5-HT4 Receptor Agonists / pharmacology
  • Serotonin 5-HT4 Receptor Agonists / therapeutic use*
  • Solubility
  • Task Performance and Analysis


  • Amyloid beta-Peptides
  • Aniline Compounds
  • Cholinesterase Inhibitors
  • ERG1 Potassium Channel
  • Ether-A-Go-Go Potassium Channels
  • Ligands
  • Piperidines
  • Serotonin 5-HT4 Receptor Agonists
  • donecopride
  • Receptors, Serotonin, 5-HT4
  • RS 67333
  • Rhodamine 123
  • Cyclosporine