An efficient step-by-step approach to select pleiotropic drug candidates against Alzheimer's disease: The discovery of neocopride.

BackgroundThe selection of novel chemical entities that have a reasonable chance of showing clinical efficacy in AD patients is challenging.ObjectiveThe aim of this article is to outline the steps involved in a selection process that can result in the identification of potential preclinical candidates.MethodsWe used a cellular model of injured hippocampal neurons, for the validation of the association of the targets considered (acetylcholinesterase and 5-HT4 receptor) and for the selection of multi-target ligands active in cellulo. The mechanism of the plural action of the best compound, we called neocopride, was deciphered using several in cellulo approaches. Finally, the protective effect of neocopride against short-term memory impairment was investigated in mice intoxicated with amyloid- β peptide.ResultsOur results show that neocopride displays strong protective effects against short-term memory disorders after oral administration at a dose of 3 mg/kg.ConclusionsThe findings suggest that neocopride is a promising drug candidate It is currently undergoing preclinical regulatory trials for AD.