Effect of tissue-specific acetylcholinesterase inhibitor C-547 on α3β4 and αβεδ acetylcholine receptors in COS cells

Lindovský, Jiří; Петров, К. А.; Krůšek, Jan; Резник, В. С.; Nikolsky, E. E.; Vyskočil, F.

doi:10.1016/j.ejphar.2012.05.010

Cited by 5 publications

(1 citation statement)

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“…To ensure a peripheral effect and prevent blood‒brain barrier (BBB) crossing and, hence, potential central cholinergic side-effects, the design of novel AChEIs against myasthenia gravis is commonly based on the introduction of permanently charged quaternary nitrogens [ 9 ]. A number of alkylammonium [ 10 ], piperidinium [ 11 , 12 ], pyridinium [ 13 ], quinolinium [ 14 ], and isoquinolinium [ 15 ] derivatives have been developed as potential drug candidates against myasthenia gravis or as reversal agents of neuromuscular blockade in surgical anesthesia. These compounds usually exhibit AChE inhibitory potencies in the low micromolar to low nanomolar range.…”

Section: Introductionmentioning

confidence: 99%

Increasing Polarity in Tacrine and Huprine Derivatives: Potent Anticholinesterase Agents for the Treatment of Myasthenia Gravis

et al. 2018

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Symptomatic treatment of myasthenia gravis is based on the use of peripherally-acting acetylcholinesterase (AChE) inhibitors that, in some cases, must be discontinued due to the occurrence of a number of side-effects. Thus, new AChE inhibitors are being developed and investigated for their potential use against this disease. Here, we have explored two alternative approaches to get access to peripherally-acting AChE inhibitors as new agents against myasthenia gravis, by structural modification of the brain permeable anti-Alzheimer AChE inhibitors tacrine, 6-chlorotacrine, and huprine Y. Both quaternization upon methylation of the quinoline nitrogen atom, and tethering of a triazole ring, with, in some cases, the additional incorporation of a polyphenol-like moiety, result in more polar compounds with higher inhibitory activity against human AChE (up to 190-fold) and butyrylcholinesterase (up to 40-fold) than pyridostigmine, the standard drug for symptomatic treatment of myasthenia gravis. The novel compounds are furthermore devoid of brain permeability, thereby emerging as interesting leads against myasthenia gravis.

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