Laurent Lecanu, Laurent Tillement, Althea McCourty, Georges Rammouz, Wenguo Yao, Janet Greeson and Vassilios Papadopoulos Pages 123 - 140 ( 18 )
We report herein the synthesis and biological evaluation of dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy- 6-(4-ethyl-piperazine-1-carbonyl)-phenyl ester (SP-04), a new drug candidate that is designed to offer a multi-target therapeutic neuroprotective approach as a treatment for Alzheimer ’ s disease (AD). SP-04 inhibits acetylcholinesterase (AchE) activity both in vitro and in vivo, and induces a dose-dependent increase in Ach levels. SP-04 releases the metabolite 4-(4-ethyl-piperazin-1-yl)-1-(2,3,4-trihydroxy-phenyl)-butan-1-one (SP-04m). Both SP-04 and SP-04m are 1-receptor antagonists supporting their interest in relieving symptoms related to psychosis, a non-cognitive condition often associated with AD. SP-04m displays important antioxidant properties and both SP-04 and SP-04m offers neuroprotection against Aβ1-42 toxicity in various neuronal cell lines. In addition, both SP-04 and SP-04m protect neuronal cells and rat brain mitochondria exposed to various mitochondrial respiratory chain complex toxins. Taken together these data suggest that the SP-04 multi-targeting approach might offer a novel therapeutic strategy for the treatment of AD.
Acetylcholinesterase inhibitor, Alzheimer's disease, Antioxidant, Blood-brain barrier, Microdialysis, Mitochondria, Prodrug, Sigma-1 receptor
Research Institute of the McGill University Health Centre and the Departments of Medicine, Biochemistry and Pharmacology&Therapeutics, McGill University, 1650 Cedar Avenue, C10-148, Montreal, Quebec H3G 1A4, Canada.