title: Neuroprotective Tri- and Tetracyclic BChE Inhibitors Releasing Reversible Inhibitors upon Carbamate Transfer.
abstract: Tri- and tetracyclic nitrogen-bridgehead compounds were designed and synthesized to yield micromolar cholinesterase (ChE) inhibitors. Structure-activity relationships identified potent compounds with butyrylcholinesterase selectivity. These compounds were selected as starting points for the design and synthesis of carbamate-based (pseudo)irreversible inhibitors. Compounds with superior inhibitory activity and selectivity were obtained and kinetically characterized also with regard to the velocity of enzyme carbamoylation. Structural elements were identified and introduced that additionally showed neuroprotective properties on a hippocampal neuronal cell line (HT-22) after glutamate-induced intracellular reactive oxygen species generation. We have identified potent and selective pseudoirreversible butyrylcholinesterase inhibitors that release reversible inhibitors with neuroprotective properties after carbamate transfer to the active site of cholinesterases.
authors.affiliation: Institut für Pharmazie, Universität Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Fouad H
authors.initials: FH
authors.lastname: Darras
authors.affiliation: Institut für Pharmazie, Universität Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Beata
authors.initials: B
authors.lastname: Kling
authors.affiliation: Institut für Pharmazie, Universität Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.affiliation: Institut für Pharmazie, Universität Regensburg , Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
keywords: Alzheimer's disease; butyrylcholinesterase; carbamates; neuroprotection