Donecopride, a Swiss army knife with potential against Alzheimer's disease

Abstract

Background and Purpose:We recently identified donecopride as a pleiotropic compound able to inhibit AChE and to activate 5-HT 4 receptors. Here, we have assessed the potential therapeutic effects of donecopride in treating Alzheimer's disease (AD).Experimental Approach: We used two in vivo animal models of AD, transgenic 5XFAD mice and mice exposed to soluble amyloid-β peptides and, in vitro, primary cultures of rat hippocampal neurons. Pro-cognitive and anti-amnesic effects were evaluated with novel object recognition, Y-maze, and Morris water maze tests. Amyloid load in mouse brain was measured ex vivo and effects of soluble amyloid-β peptides on neuronal survival and neurite formation determined in vitro.Key Results: In vivo, chronic (3 months) administration of donecopride displayed potent anti-amnesic properties in the two mouse models of AD, preserving learning capacities, including working and long-term spatial memories. These behavioural effects were accompanied by decreased amyloid aggregation in the brain of 5XFAD mice and, in cultures of rat hippocampal neurons, reduced tau hyperphosphorylation.In vitro, donecopride increased survival in neuronal cultures exposed to soluble amyloid-β peptides, improved the neurite network and provided neurotrophic benefits, expressed as the formation of new synapses.Conclusions and Implications: Donecopride acts like a Swiss army knife, exhibiting a range of sustainable symptomatic therapeutic effects and potential diseasemodifying effects in models of AD. Clinical trials with this promising drug candidate will soon be undertaken to confirm its therapeutic potential in humans.

Therapeutic modulators of the serotonin 5-HT4 receptor: a patent review (2014-present)

“…This compound is also patented for Table 1). The replacement of the amide by a ketone or an oxadiazole ring appears as an interesting strategy in order to optimize the central distribution of 5-HT 4 R ligand for treatment of CNS pathologies [65,66]. It is also worth to note that novelty in terms of structures could rely in the introduction of deuterium atom in place of hydrogen on known ligands and could finally lead to an improvement in metabolic stability [39].…”

Novel and atypical pathways for serotonin signaling

“…Indeed, whereas agonist-independent 5-HT 4 receptor-operated Gs signaling is inhibited by the inverse agonists RO 116-0086 and RO 116-2617, these compounds are inactive on receptor-dependent ADAM10 activation 42 . Chronic administration of RS 67333, a 5-HT 4 receptor agonist, or donecopride, a multi-target compound able to both inhibit acetylcholinesterase and activate 5-HT 4 receptors, decreases amyloid load and Tau hyperphosphorylation as well as learning and memory deficits in mouse models of Alzheimer's disease 43 , 44 .…”

Multidirectional in vitro and in cellulo studies as a tool for identification of multi-target-directed ligands aiming at symptoms and causes of Alzheimer’s disease

“…Among them, we identified 12 inhibitors of tau and Ab aggregation with the inhibitory potency exceeding 50%. Most compounds with such dual inhibitory activity are tacrine (5,17,20,(27)(28)(29)(30) and N-benzylpiperidine (16, 37-39) derivatives. Tacrine is a widely used scaffold in the AD therapy research 40 .…”

“…The most explored multifunctional ligands combine anticholinesterase activity with anti-aggregation properties resulting from inhibition of b-secretase or modulation of c-secretase and direct inhibition of processes of aggregation of Ab and tau proteins [15][16][17][18] . Also, many G-protein coupled receptors are explored in combination with anticholinesterase activity, among them cannabinoid receptors CB 1 and CB 2 19-22 , histamine H 3 receptors [23][24][25] or serotonin 5-HT 1A 26 , 5-HT 4 , and 5-HT 6 receptors [27][28][29][30][31] . Here, we present the broadened in vitro and in cellulo studies on the activity of the previously published first-in-class multi-target-directed ligands ( Figure 1) targeting serotonergic 5-HT 6 receptors and cholinesterases 30,31 .…”