title: Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents.
abstract: Alzheimer's disease (AD) is a prevalent neurodegenerative disorder with multifactorial causes that requires multitargeted treatment. Inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) improve cholinergic signaling in the central nervous system and thus AChE inhibitors are well established in the therapy of AD to improve memory disturbances and other cognitive symptoms. On the other hand, AD patients benefit from reduction of pathologic glutamate-induced, Ca(2+)-mediated excitotoxicity by the N-methyl-d-aspartate receptor (NR) antagonist memantine. New drugs that simultaneously affect both cholinergic transmission and glutamate-induced excitotoxicity may further improve AD treatment. While connecting beta-carboline units by alkylene spacers in two different series of compounds and subsequent evaluation of their AChE/BChE-inhibitory potential, we found that several of these bivalent beta-carbolines were potent NR blockers. The most promising compound was a N(9)-homobivalent beta-carboline with a nonylene spacer, which displayed IC(50) values of 0.5 nM for AChE, 5.7 nM for BChE, and 1.4 microM for NR, respectively.
authors.affiliation: Institut fur Pharmazie, Lehrstuhl fur Pharmazeutische/Medizinische Chemie, Friedrich-Schiller-Universitat Jena, Germany.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Rook
authors.forename: Kai-Uwe
authors.initials: KU
authors.lastname: Schmidtke
authors.forename: Friedemann
authors.initials: F
authors.lastname: Gaube
authors.forename: Dirk
authors.initials: D
authors.lastname: Schepmann
authors.forename: Bernhard
authors.initials: B
authors.lastname: Wünsch
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.forename: Jochen
authors.initials: J
authors.lastname: Lehmann
authors.forename: Thomas
authors.initials: T
authors.lastname: Winckler
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy*; D002091:Butyrylcholinesterase / Q000187:drug effects; D002243:Carbolines / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D020128:Inhibitory Concentration 50; D008559:Memantine; D019636:Neurodegenerative Diseases / Q000188:drug therapy; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
chemical_list: D002243:Carbolines; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D002091:Butyrylcholinesterase; D008559:Memantine