دورية أكاديمية
Novel piperazine derivative PMS1339 exhibits tri-functional properties and cognitive improvement in mice.
| العنوان: | Novel piperazine derivative PMS1339 exhibits tri-functional properties and cognitive improvement in mice. |
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| المؤلفون: | Miezan Ezoulin JM; Department of Pharmacology, Institute of Medical Sciences, Shanghai Jiao Tong University School of Medicine, Shanghai, P.R. China., Shao BY, Xia Z, Xie Q, Li J, Cui YY, Wang H, Dong CZ, Zhao YX, Massicot F, Qiu ZB, Heymans F, Chen HZ |
| المصدر: | The international journal of neuropsychopharmacology [Int J Neuropsychopharmacol] 2009 Nov; Vol. 12 (10), pp. 1409-19. Date of Electronic Publication: 2009 May 22. |
| نوع المنشور: | Comparative Study; Journal Article; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Oxford University Press Country of Publication: England NLM ID: 9815893 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1469-5111 (Electronic) Linking ISSN: 14611457 NLM ISO Abbreviation: Int J Neuropsychopharmacol Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: 2015- : Oxford Oxford University Press Original Publication: Cambridge, [England] : Cambridge University Press, |
| مواضيع طبية MeSH: | Cognition/*drug effects , Cognition/*physiology , Cognition Disorders/*drug therapy , Piperazines/*chemistry , Piperazines/*therapeutic use, Acetylcholinesterase/metabolism ; Animals ; Cell Line, Tumor ; Cholinesterase Inhibitors/chemistry ; Cholinesterase Inhibitors/metabolism ; Cholinesterase Inhibitors/therapeutic use ; Cognition Disorders/enzymology ; Drug Delivery Systems ; Electrophorus/metabolism ; Humans ; Male ; Memory/drug effects ; Memory/physiology ; Mice ; Piperazine ; Piperazines/metabolism ; Piperazines/pharmacology ; Rabbits |
| مستخلص: | 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. |
| المشرفين على المادة: | 0 (Cholinesterase Inhibitors) 0 (PMS1339) 0 (Piperazines) 1RTM4PAL0V (Piperazine) EC 3.1.1.7 (Acetylcholinesterase) |
| تواريخ الأحداث: | Date Created: 20090523 Date Completed: 20100629 Latest Revision: 20181201 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1017/S1461145709000455 |
| PMID: | 19460190 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1469-5111 |
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| DOI: | 10.1017/S1461145709000455 |