title: Novel piperazine derivative PMS1339 exhibits tri-functional properties and cognitive improvement in mice.
abstract: Amyloid-beta-induced neuroinflammation plays a central role in the extensive loss of cholinergic neurons and cognitive decline in Alzheimer's disease. The acetylcholinesterase (AChE) inhibitors are the first class of drugs used to enhance surviving cholinergic activities. However, their limited effectiveness following long-term treatment raises a need for new multi-target therapies. We report herein a novel piperazine derivative compound PMS1339 possesses multifunctional properties including anti-platelet-activating factor, AChE inhibition, Abeta aggregation inhibition and cognitive improvement. PMS1339 could significantly inhibit both mice brain AChE (IC50=4.41+/-0.63 microM) and sera butyrylcholinesterase (BuChE, IC50=1.09+/-0.20 microM). PMS1339 was also found to inhibit neuronal AChE secreted by SH-SY5Y cell line (IC50=17.95+/-2.31 microM). Enzyme kinetics experiments performed on electric eel AChE indicated that PMS1339 acts as a mixed type competitive AChE inhibitor. Molecular docking studies using the X-ray crystal structure of AChE from Torpedo californica elucidated the interactions between PMS1339 and AChE: PMS1339 is well buried inside the active-site gorge of AChE interacting with Trp84 at the bottom, Tyr121 halfway down and Trp279 at the peripheral anionic site (PAS). Thioflavin T-based fluorimetric assay revealed the ability of PMS1339 to inhibit AChE-induced Abeta aggregation. In-vivo study indicated PMS1339 (1 mg/kg i.p.) reversed scopolamine-induced memory impairment in mice. Overall, these findings indicated that PMS1339 exhibits tri-functional properties in vitro and cognitive improvement in vivo, and revealed the emergence of a multi-target-directed ligand to tackle the determinants of Alzheimer's disease.
authors.affiliation: Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China.
authors.forename: Jean Marc
authors.initials: JM
authors.lastname: Miezan Ezoulin
authors.forename: Bi-Yun
authors.initials: BY
authors.lastname: Shao
authors.forename: Zheng
authors.initials: Z
authors.lastname: Xia
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.forename: Juan
authors.initials: J
authors.lastname: Li
authors.forename: Yong-Yao
authors.initials: YY
authors.lastname: Cui
authors.forename: Hao
authors.initials: H
authors.lastname: Wang
authors.forename: Chang-Zhi
authors.initials: CZ
authors.lastname: Dong
authors.forename: Yan-Xing
authors.initials: YX
authors.lastname: Zhao
authors.forename: France
authors.initials: F
authors.lastname: Massicot
authors.forename: Zhui-Bai
authors.initials: ZB
authors.lastname: Qiu
authors.forename: Françoise
authors.initials: F
authors.lastname: Heymans
authors.forename: Hong-Zhuan
authors.initials: HZ
authors.lastname: Chen
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use; D003071:Cognition / Q000187:drug effects* / Q000502:physiology*; D003072:Cognition Disorders / Q000188:drug therapy* / Q000201:enzymology; D016503:Drug Delivery Systems; D004593:Electrophorus / Q000378:metabolism; D006801:Humans; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D051379:Mice; D000077489:Piperazine; D010879:Piperazines / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011817:Rabbits
chemical_list: D002800:Cholinesterase Inhibitors; C550385:PMS1339; D010879:Piperazines; D000077489:Piperazine; D000110:Acetylcholinesterase