Development of an Efficient Therapeutic Agent for Alzheimer's Disease: Design and Synthesis of Dual Inhibitors of Acetylcholinesterase and Serotonin Transporter

To date, acetylcholinesterase (AChE) inhibitors have been clinically effective drugs for the palliative treatment Alzheimer's disease. but their clinical efficacy is limited, mainly fine to their adverse effects oil peripheral organs. Since patients of Alzheimer's disease of in exhibit depression as well as memory impairment. dual inhibitors of AChE and serotonin transporter (SERT) would be a better therapeutic method. Anti-depressive effects based oil SERT inhibition would reduce the dose-related side effects of AChE, inhibitors. Such dual inhibitors were designed by the hybridization of rivastigmine and fluoxetine based on a hypothetical model of the AChE. active site. Various derivatives were synthesized and evaluated for their in vitro inhibition, and then (S)-5j (RS-1259), which possessed balanced inhibitory activities of AChE (IC50 = 101 nM) and SERT (IC50 = 42 nM), Was successfully obtained. An ex vivo experiment in mice indicated that (S)-5j (RS-1259) simultaneously inhibited AChE and SERT in file brain following an oral administration. The simultaneous elevation of extracellular levels of acetylcholine and serotonin ill the rat hippocampus was actually confirmed by microdialysis.