Bivalent β-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.

Stabilizers of Neuronal and Mitochondrial Calcium Cycling as a Strategy for Developing a Medicine for Alzheimer's Disease

“…80 Bivalent β-carboline compound blocked AChE as well as the [Ca 2+ ] c transients elicited by glutamate by inhibiting NMDARs. 81 Destabilization of microctubules through tau hyperphosphorylation distorts axonal transport and contributes to neuronal death in AD. 82 Such hyperphosphorylation is carried out by various kinases, i.e.…”

Navigating the Chemical Space of Multitarget-Directed Ligands: From Hybrids to Fragments in Alzheimer’s Disease

“…Despite previous studies having already reported on dual AChE/NMDAR compounds [28,29], this was the first time that two marketed drugs were rationally combined in a single new chemical entity.…”

Conformationally constrained NR2B selective NMDA receptor antagonists derived from ifenprodil: Synthesis and biological evaluation of tetrahydro-3-benzazepine-1,7-diols

“…Different concentrations of the test compounds 25 and cis-32 were added 30 min before addition of (S)-glutamate and glycine and the released amount of LDH was measured. 36 In Figure 2 the inhibition of glutamate/glycine induced excitotoxicity at different concentrations of phenols 25, cis-32 and methyl ether 2a is compared. The phenylbutyl derivative 25 reduced the excitotoxicity with an IC 50 -value of 18.4 nM.…”