title: A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Aβ25-35-impaired mouse cognitive function.
abstract: BACKGROUND
  The mechanism involved in AD is complex, which has prompted to develop compounds that could simultaneously interact with several potential targets. Here, we report a new synthesized compound SCR-1693 which is designed to target both AChE and calcium channels that are potential for AD therapy.
  
  
  OBJECTIVE
  We investigated the effects of SCR-1693 on AChE and calcium channels, the effects of neuroprotection and anti-amnesia in icv-Aβ25-35-injected mice, and the potential mechanisms.
  
  
  METHODS
  AChE activity assay, intracellular Ca(2+) content and calcium currents measurement, and Aβ25-35-induced cellular death determine were performed for validation of designed targets and neuroprotection of SCR-1693. Mice were orally administrated with SCR-1693 once daily after an Aβ25-35 injection. The Morris water maze and Y-maze test, and hippocampal protein detection were conducted on days 5-10, day 11, and day 8. The pyramidal neuron number, hippocampal AChE activity, and synaptic transmission were measured on day 12.
  
  
  RESULTS
  SCR-1693 acted as a selective, reversible, and noncompetitive inhibitor of AChE, and a nonselective voltage-gated calcium channel blocker. SCR-1693 also inhibited the increase of AChE activity in the mouse hippocampus. SCR-1693 was more effective than donepezil and memantine in preventing Aβ25-35-induced long-term and short-term memory impairment, maintaining the basal transmission of Schaffer collateral-CA1 synapses, and sustaining LTP in mouse hippocampus. SCR-1693 attenuated Aβ25-35-induced death of SH-SY5Y cell and the loss of hippocampal pyramidal neurons, and regulated Aβ25-35-induced signal cascade in neurons.
  
  
  CONCLUSIONS
  All these findings indicated that SCR-1693, as a double-target-direction agent, is a considerable candidate for AD therapy.
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, People's Republic of China.|Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, 210042, People's Republic of China.
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, 210042, People's Republic of China.
authors.forename: Rong
authors.initials: R
authors.lastname: Chen
authors.affiliation: Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, 210042, People's Republic of China.
authors.forename: Wenji
authors.initials: W
authors.lastname: An
authors.affiliation: Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, 210042, People's Republic of China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Wang
authors.affiliation: Jiangsu Simovay Pharmaceutical Co., Ltd., Nanjing, 210042, People's Republic of China.
authors.forename: Gaoyong
authors.initials: G
authors.lastname: Liao
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, People's Republic of China.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, People's Republic of China.
authors.forename: Aijing
authors.initials: A
authors.lastname: Bi
authors.affiliation: Jiangsu Province Key Laboratory for Molecular and Medicine Biotechnology, College of Life Science, Nanjing Normal University, Nanjing, 210046, People's Republic of China. yinzhimin@njnu.edu.cn.
authors.forename: Zhimin
authors.initials: Z
authors.lastname: Yin
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, 210093, People's Republic of China. lanluo@nju.edu.cn.
authors.forename: Lan
authors.initials: L
authors.lastname: Luo
mesh_terms: D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D000818:Animals; D016466:CHO Cells; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002800:Cholinesterase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D003071:Cognition / Q000187:drug effects / Q000502:physiology; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008813:Mice, Inbred ICR; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000633:toxicity*; D051381:Rats; D017208:Rats, Wistar; D013619:Tacrine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D002800:Cholinesterase Inhibitors; D010446:Peptide Fragments; C000600497:SCR1693; C074636:amyloid beta-protein (25-35); D013619:Tacrine
keywords: AChE inhibitor; Learning and memory; Neuroprotection; SCR-1693; VGCCs blocker; β-Amyloid