Design, synthesis and evaluation of novel dual monoamine-cholinesterase inhibitors as potential treatment for Alzheimer’s disease

• Published in: Neuropharmacology Vol. 109; pp. 376 - 385
• Main Authors: Liu, Wei, Lang, Ming, Youdim, Moussa B.H., Amit, Tamar, Sun, Yewei, Zhang, Zaijun, Wang, Yuqiang, Weinreb, Orly
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2016
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer’s disease; Animals; Brain - drug effects; Brain - metabolism; Cell Line, Tumor; Cholinesterase inhibition; Cholinesterase Inhibitors - administration & dosage; Cholinesterase Inhibitors - chemical synthesis; Dose-Response Relationship, Drug; Drug Combinations; Drug Design; Humans; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors - administration & dosage; Monoamine Oxidase Inhibitors - chemical synthesis; Monoamine oxidase-A inhibition; Multifunctional drug; Neuroprotection; Rats; Rats, Sprague-Dawley; Treatment Outcome; Neuroprotection; AChE; ChE; AChEIs; AD; BBB; Alzheimer’s disease; DOPAC; OS; ACh; Multifunctional drug; HVA; Cholinesterase inhibition; 5-HIAA; Monoamine oxidase-A inhibition; 3-MT; NE; ROS; MAO; 5-HT; DA; HPLC
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2016.06.013

Current novel therapeutic approach suggests that multifunctional compounds with diverse biological properties and a single bioavailability and pharmacokinetic metabolism, will produce higher significant advantages in treatment of neurodegenerative diseases, such as Alzheimer’s disease (AD). Based on this rational, a new class of cholinesterase (ChE)-monoamine oxidase (MAO) inhibitors were designed and synthesized by amalgamating the propargyl moiety of the irreversible selective MAO-B inhibitor, neuroprotective/neurorestorative anti-Parkinsonian drug, rasagiline, into the “N-methyl” position of the ChE inhibitor, anti-AD drug rivastigmine. Initially, we examined the MAO and ChE inhibitory effect of these novel compounds, MT series in vitro and in vivo. Among MT series, MT-031 exhibited higher potency as a dual MAO-A and ChE inhibitor compared to other compounds in acute-treated mice. Additionally, MT-031 was found to increase the striatal levels of dopamine (DA), serotonin (5-HT) and norepinephrine (NE), and prevent the metabolism of DA and 5-HT. Finally, we have demonstrated that MT-031 exerted neuroprotective effect against H2O2-induced neurotoxicity and reactive oxygen species generation in human neuroblastoma SH-SY5Y cells. These findings provide evidence that MT-031 is a potent brain permeable novel multifunctional, neuroprotective and MAO-A/ChE inhibitor, preserves in one molecule entity some of the beneficial properties of its parent drugs, rasagiline and rivastigmine, and thus may be indicated as novel therapeutic approach for AD. •A new class of ChE-MAO inhibitors were designed and synthesized.•A lead compound MT-031 is brain permeable and dual MAO-A and AChE/BuChE inhibitor.•MT-031 regulates striatal levels of monoamines.•MT-031 exerts neuroprotective effect against H2O2-induced neurotoxicity.