Novel Piperidinium and Pyridinium Agents as Water-Soluble Acetylcholinesterase Inhibitors for the Reversal of Neuromuscular Blockade

Palin, Ronald; Clark, John K.; Cowley, Phill; Muir, Alan W.; Pow, Eleanor; Prosser, Alan; Taylor, Robert T.; Zhang, Ming‐Qiang

doi:10.1016/s0960-894x(02)00483-3

Cited by 28 publications

(10 citation statements)

References 5 publications

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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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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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“…As these compounds contain quaternary ammonium moieties, they have limited permeability through the blood-brain barrier [9,10]. Furthermore, they may be used as prophylaxis against OPCs or as new drugs for the treatment of Myasthenia gravis, and in anesthetic practice to reverse the skeletal muscle relaxation induced by non-depolarizing neuromuscular blocking agents [11]. …”

Section: Introductionmentioning

confidence: 99%

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

Šepsová

Karasová

Korábečný

et al. 2013

IJMS

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Acetylcholinesterase (AChE) reactivators were developed for the treatment of organophosphate intoxication. Standard care involves the use of anticonvulsants (e.g., diazepam), parasympatolytics (e.g., atropine) and oximes that restore AChE activity. However, oximes also bind to the active site of AChE, simultaneously acting as reversible inhibitors. The goal of the present study is to determine how oxime structure influences the inhibition of human recombinant AChE (hrAChE). Therefore, 24 structurally different oximes were tested and the results compared to the previous eel AChE (EeAChE) experiments. Structural factors that were tested included the number of pyridinium rings, the length and structural features of the linker, and the number and position of the oxime group on the pyridinium ring.

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“…The synthesis used in this study is a practical procedure that permits us to prepare very beautiful crystalline dyes 2 – 4 (R1 = H, phenyl) from Zincke salts ( DNP) 2,4‐dinitrophenyl 1 and secondary amines diethylamine or pyrrolidine according to Scheme . Pyridinium salts are a versatile class of compounds used as phase transfer catalysts,16 initiators of cationic polymerization,17 wide range antimicrobials,18 enzyme inhibitors,19, 20 acylating agents,21 dyes, and cationic surfactants 22. Their chiral representatives, that is, pyridinium salts containing a chiral auxiliary group linked to the ring nitrogen, have been largely used as starting materials in asymmetric synthesis to obtain substituted chiral dihydropyridines,23 tetrahydropyridines,24 piperidines,25 and nitrogenated complex compounds such as natural alkaloids26 and synthetic candidates for drugs 20…”

Section: Resultsmentioning

confidence: 99%

Photochromic behavior of several new synthesized dyes via Zincke salts

Mahmoodi

Mamaghani

Ghanadzadeh

et al. 2009

J of Physical Organic Chem

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Novel Piperidinium and Pyridinium Agents as Water-Soluble Acetylcholinesterase Inhibitors for the Reversal of Neuromuscular Blockade

Cited by 28 publications

References 5 publications

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

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

Oximes: Inhibitors of Human Recombinant Acetylcholinesterase. A Structure-Activity Relationship (SAR) Study

Photochromic behavior of several new synthesized dyes via Zincke salts

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