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.

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Background: Extracts from the rhizome of Cimicifuga racemosa (black cohosh) are increasingly popular as herbal alternative to hormone replacement therapy (HRT) for the alleviation of postmenopausal disorders. However, the molecular mode of action and the active principles are presently not clear. Previously published data have been largely contradictory. We, therefore, investigated the effects of a lipophilic black cohosh rhizome extract and cycloartane-type triterpenoids on the estrogen receptor positive human breast cancer cell line MCF-7.

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A chiral pool synthesis was developed to obtain all four stereoisomeric 2-methyl-3-(4-phenylbutyl)tetrahydro-3-benzazepin-1-ols 21, 31, and 32 in a seven- to eight-step sequence. The phenols 32 reveal slightly higher GluN2B affinity than the methyl ethers 21. The GluN2B affinity increases in the order (1R,2S) < (1S,2S) < (1S,2R) < (1R,2R). The stereoisomeric phenols (R,R)-32 and (S,R)-32 show the highest GluN2B affinity and the highest cytoprotective activity. Both compounds represent GluN2B selective allosteric NMDA receptor antagonists. Docking of the 3-benzazepin-1-ols into the ifenprodil binding site of the crystallized GluN1b/GluN2B N-terminal domains led to free binding energies, which correlate nicely with the experimentally determined GluN2B affinities. The similar GluN2B affinity of the stereoisomeric phenols (S,S)-32, (R,R)-32, and (S,R)-32 is explained by different binding modes of the 3-benzazepine scaffold. The benzyl ethers 31 reveal unexpectedly high GluN2B affinity but do not show cytoprotective effects. The additional benzyl moiety of 31 binds into a previously unrecognized lipophilic subpocket.