Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents.
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.
Rook
Yvonne
Y
Institut fur Pharmazie, Lehrstuhl fur Pharmazeutische/Medizinische Chemie, Friedrich-Schiller-Universitat Jena, Germany.
Schmidtke
Kai-Uwe
KU
Gaube
Friedemann
F
Schepmann
Dirk
D
Wünsch
Bernhard
B
Heilmann
Jörg
J
Lehmann
Jochen
J
Winckler
Thomas
T
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*
D002243:Carbolines; D002800:Cholinesterase Inhibitors; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D002091:Butyrylcholinesterase; D008559:Memantine