td-5108 and donecopride

Pleiotropic intervention may be a requirement for effective limitation of the progression of multifactorial diseases such as Alzheimer's Disease. One approach to such intervention is to design a single chemical entity capable of acting on two or more targets of interest, which are accordingly known as Multi-Target Directed Ligands (MTDLs). We recently described donecopride, the first MTDL able to simultaneously inhibit acetylcholinesterase and act as an agonist of the 5-HT

Topics: Acetylcholinesterase; Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Crystallography, X-Ray; Drug Design; Humans; Indoles; Ligands; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Torpedo

In this work, we describe the synthesis and in vitro evaluation of a novel series of multitarget-directed ligands (MTDL) displaying both nanomolar dual-binding site (DBS) acetylcholinesterase inhibitory effects and partial 5-HT4R agonist activity, among which donecopride was selected for further in vivo evaluations in mice. The latter displayed procognitive and antiamnesic effects and enhanced sAPPα release, accounting for a potential symptomatic and disease-modifying therapeutic benefit in the treatment of Alzheimer's disease.

Topics: Alzheimer Disease; Aniline Compounds; Animals; Cholinesterase Inhibitors; Computer Simulation; Crystallography, X-Ray; Drug Design; Drug Evaluation, Preclinical; Guinea Pigs; Humans; Ligands; Male; Memory, Short-Term; Mice, Inbred C57BL; Mice, Inbred Strains; Molecular Targeted Therapy; Piperidines; Receptors, Serotonin, 5-HT4; Serotonin 5-HT4 Receptor Agonists; Structure-Activity Relationship; Toxicity Tests, Acute

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.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Aniline Compounds; Animals; Brain; Chlorocebus aethiops; Cholinesterase Inhibitors; Cognition; COS Cells; Cyclosporine; Drug Design; ERG1 Potassium Channel; Ether-A-Go-Go Potassium Channels; Kinetics; Ligands; Mice; Permeability; Piperidines; Receptors, Serotonin, 5-HT4; Rhodamine 123; Serotonin 5-HT4 Receptor Agonists; Solubility; Task Performance and Analysis