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Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M1 and M2.

ABSTRACT: A set of hybrid compounds composed of the fragment of allosteric modulators of the muscarinic receptor, i.e. W84 and naphmethonium, and the well-known AChE inhibitor tacrine on the one hand, and the skeletons of the orthosteric muscarinic agonists, iperoxo and isox, on the other hand, were synthesized. The two molecular moieties were connected via a polymethylene linker of varying length. These bipharmacophoric compounds were investigated for inhibition of AChE (from electric eel) and BChE (from equine serum) as well as human ChEs in vitro and compared to previously synthesized dimeric inhibitors. Among the studied hybrids, compound 10-C10, characterized by a 10 carbon alkylene linker connecting tacrine and iperoxo, proved to be the most potent inhibitor with the highest pIC50 values of 9.81 (AChE from electric eel) and 8.75 (BChE from equine serum). Docking experiments with compounds 10-C10, 7b-C10, and 7a-C10 helped to interpret the experimental inhibitory power against AChE, which is affected by the nature of the allosteric molecular moiety, with the tacrine-containing hybrid being much more active than the naphthalimido- and phthalimido-containing analogs. Furthermore, the most active AChE inhibitors were found to have affinity to M1 and M2 muscarinic receptors. Since 10-C10 showed almost no cytotoxicity, it emerged as a promising lead structure for the development of an anti-Alzheimer drug.

SUBMITTER: Messerer R

PROVIDER: S-EPMC6072511 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M1 and M2.

Messerer Regina R Dallanoce Clelia C Matera Carlo C Wehle Sarah S Flammini Lisa L Chirinda Brian B Bock Andreas A Irmen Matthias M Tränkle Christian C Barocelli Elisabetta E Decker Michael M Sotriffer Christoph C De Amici Marco M Holzgrabe Ulrike U

MedChemComm 20170427 6

A set of hybrid compounds composed of the fragment of allosteric modulators of the muscarinic receptor, i.e. W84 and naphmethonium, and the well-known AChE inhibitor tacrine on the one hand, and the skeletons of the orthosteric muscarinic agonists, iperoxo and isox, on the other hand, were synthesized. The two molecular moieties were connected via a polymethylene linker of varying length. These bipharmacophoric compounds were investigated for inhibition of AChE (from electric eel) ...[more]

PMID: 30108847

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Project description:UnlabelledCholinergic vulnerability, characterized by loss of acetylcholine (ACh), is one of the hallmarks of Alzheimer's disease (AD). Previous work has suggested that decreased ACh activity in AD may contribute to pathological changes through global alterations in alternative splicing. This occurs, at least partially, via the regulation of the expression of a critical protein family in RNA processing, heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins. These proteins regulate several steps of RNA metabolism, including alternative splicing, RNA trafficking, miRNA export, and gene expression, providing multilevel surveillance in RNA functions. To investigate the mechanism by which cholinergic tone regulates hnRNPA2/B1 expression, we used a combination of genetic mouse models and in vivo and in vitro techniques. Decreasing cholinergic tone reduced levels of hnRNPA2/B1, whereas increasing cholinergic signaling in vivo increased expression of hnRNPA2/B1. This effect was not due to decreased hnRNPA2/B1 mRNA expression, increased aggregation, or degradation of the protein, but rather to decreased mRNA translation by nonsense-mediated decay regulation of translation. Cell culture and knock-out mice experiments demonstrated that M1 muscarinic signaling is critical for cholinergic control of hnRNPA2/B1 protein levels. Our experiments suggest an intricate regulation of hnRNPA2/B1 levels by cholinergic activity that interferes with alternative splicing in targeted neurons mimicking deficits found in AD.Significance statementIn Alzheimer's disease, degeneration of basal forebrain cholinergic neurons is an early event. These neurons communicate with target cells and regulate their long-term activity by poorly understood mechanisms. Recently, the splicing factor hnRNPA2/B, which is decreased in Alzheimer's disease, was implicated as a potential mediator of long-term cholinergic regulation. Here, we demonstrate a mechanism by which cholinergic signaling controls the translation of hnRNPA2/B1 mRNA by activation of M1 muscarinic type receptors. Loss of cholinergic activity can have profound effects in target cells by modulating hnRNPA2/B1 levels.

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Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M1 and M2.

Publications

Novel bipharmacophoric inhibitors of the cholinesterases with affinity to the muscarinic receptors M<sub>1</sub> and M<sub>2</sub>.

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