Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents.

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Rook Y, Schmidtke KU, Gaube F, Schepmann D, Wunsch B, Heilmann J, Lehmann J, Winckler T

Bivalent beta-carbolines as potential multitarget anti-Alzheimer agents.

J Med Chem. 2010 May 13;53(9):3611-7. doi: 10.1021/jm1000024.

PubMed ID
20361801 [ View in PubMed
]
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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
MemantineGlutamate receptor ionotropic, NMDA 1IC 50 (nM)5600N/AN/ADetails
MemantineGlutamate receptor ionotropic, NMDA 1IC 50 (nM)5500N/AN/ADetails