title: Dimethyl-carbamic acid 2,3-Bis-Dimethylcarbamoyloxy-6-(4-Ethyl-Piperazine-1-Carbonyl)-phenyl ester: a novel multi-target therapeutic approach to neuroprotection.
abstract: 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 s1-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 Ab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.
authors.affiliation: The 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.
authors.forename: Laurent
authors.initials: L
authors.lastname: Lecanu
authors.forename: Laurent
authors.initials: L
authors.lastname: Tillement
authors.forename: Althea
authors.initials: A
authors.lastname: McCourty
authors.forename: Georges
authors.initials: G
authors.lastname: Rammouz
authors.forename: Wenguo
authors.initials: W
authors.lastname: Yao
authors.forename: Janet
authors.initials: J
authors.lastname: Greeson
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
mesh_terms: D000110:Acetylcholinesterase; D000544:Alzheimer Disease / Q000188:drug therapy / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000138:chemical synthesis / Q000494:pharmacology; D001921:Brain / Q000187:drug effects; D002219:Carbamates / Q000138:chemical synthesis; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors; D005707:Gallic Acid / Q000031:analogs & derivatives / Q000138:chemical synthesis; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008928:Mitochondria / Q000187:drug effects; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000378:metabolism; D010879:Piperazines / Q000138:chemical synthesis; D011355:Prodrugs / Q000138:chemical synthesis; D051381:Rats; D020318:Rats, Long-Evans; D017480:Receptors, sigma / Q000037:antagonists & inhibitors*; D000097605:Sigma-1 Receptor
chemical_list: D000110:Acetylcholinesterase; D016229:Amyloid beta-Peptides; D000975:Antioxidants; D002219:Carbamates; D002800:Cholinesterase Inhibitors; D058851:GPI-Linked Proteins; D005707:Gallic Acid; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D010879:Piperazines; D011355:Prodrugs; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C558225:4-(4-ethyl-piperazin-1-yl)-1-(2,3,4-trihydroxyphenyl)butan-1-one; C075222:amyloid beta-protein (1-42); C558224:dimethyl-carbamic acid 2,3-bis-dimethylcarbamoyloxy-6-(4-ethylpiperazine-1-carbonyl)phenyl ester; C548246:Ache protein, rat