title: NO-donating tacrine hybrid compounds improve scopolamine-induced cognition impairment and show less hepatotoxicity.
abstract: A series of tacrine-NO donor hybrid compounds are synthesized and evaluated for cholinesterase inhibitory activity, cognition improving activity, and hepatotoxicity. The pharmacological results indicate that hybrid compounds 1, 2, and 3a potently inhibit cholinesterase in vitro and significantly improve the scopolamine-induced cognition impairment, whereas an analogue (3h) of 2 without the NO donor moiety does not. Compared to tacrine, 1 and 2 show much less hepatotoxicity. Molecular modeling studies suggest that 2 may interact with the catalytic and the peripheral anionic site of acetylcholinesterase.
authors.affiliation: Institute of Pharmacy, Friedrich Schiller University Jena, D-07743 Jena, Germany.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Dorothea
authors.initials: D
authors.lastname: Appenroth
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
authors.forename: Michael
authors.initials: M
authors.lastname: Kiehntopf
authors.forename: Amelie
authors.initials: A
authors.lastname: Lupp
authors.forename: Sixun
authors.initials: S
authors.lastname: Peng
authors.forename: Christian
authors.initials: C
authors.lastname: Fleck
authors.forename: Yihua
authors.initials: Y
authors.lastname: Zhang
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy; D015195:Drug Design; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D008099:Liver / Q000187:drug effects* / Q000473:pathology; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009569:Nitric Oxide / Q000737:chemistry*; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D051381:Rats; D012601:Scopolamine / Q000494:pharmacology*; D013619:Tacrine / Q000737:chemistry*
chemical_list: D018727:Muscarinic Antagonists; D020030:Nitric Oxide Donors; D009569:Nitric Oxide; D013619:Tacrine; D012601:Scopolamine; D000110:Acetylcholinesterase