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 <i>in cellulo</i>. The mechanism of the plural action of the best compound, we called neocopride, was deciphered using several <i>in cellulo</i> 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.