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

Carles Galdeano,Jacques-Philippe Colletier,Manuela Bartolini,Diego Muñoz-Torrero,Israel Silman,Ludovic Jean,Nicolas Coquelle,M Clos,Pierre-Yves Renard,Monika Cieslikiewicz-Bouet,Belén Pérez

doi:10.3390/molecules23030634

Abstract

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.

Highlights

IntroductionMyasthenia gravis is an autoimmune disease that is associated with antibodies directed against nicotinic acetylcholine receptors (AChRs) on the postsynaptic membrane at the neuromuscular junction, Molecules 2018, 23, 634; doi:10.3390/molecules23030634 www.mdpi.com/journal/moleculesMolecules 2018, 22, x or against other proteins, as muscle-specific tyrosine kinase with (MuSK), low-densityMyasthenia gravis issuch an autoimmune disease that is associated antibodies directedlipoprotein against receptor-related protein (LRP4), and agrin, which are involved in AChR clustering on the postsynaptic nicotinic acetylcholine receptors (AChRs) on the postsynaptic membrane at the neuromuscular membrane in structural maintenance of muscle-specific the neuromuscular synapseAntibodies against junction, and or against other proteins, such as tyrosine kinase[1,2].AChRs may block these receptors by binding toand the agrin, acetylcholine-binding site,inmay reduce the number lipoprotein receptor-related protein4 (LRP4), which are involved clustering on the postsynaptic membrane and in structural maintenance theactivate neuromuscular synapse cascade, [1,2].of available receptors in the membrane by internalization, andofmay the complementAntibodies against AChRs block these receptors by binding the acetylcholine-binding leading to destruction of the may postsynaptic muscle membrane and,tohence, negatively affectingsite, may reduce number available receptors in the membrane internalization, and may activate function [2,3]. the Failure of of neuromuscular transmission leads tobyfluctuating skeletal muscle fatigue complement cascade, leading to destruction membrane and, andthe weakness upon repeated contraction, whichof is the the postsynaptic main clinicalmuscle hallmark of myasthenia gravis.negatively affecting function [2,3].Failure of neuromuscular transmission leads to Weakness affects various muscle groups, such as extraocular muscles, which control eyefluctuating movements, skeletal muscle and weakness upon repeated contraction, which is the main clinical hallmark bulbar muscles infatigue the mouth and throat, responsible for speech and swallowing, and limb and axial of myasthenia gravis
The new quinolinium iodide derivatives 4–6 were prepared in good yield by reaction of tacrine, 6-chlorotacrine, and huprine Y, respectively, with excess iodomethane in refluxing methyl ethyl ketone [29] (Scheme 1)
To assess whether the two strategies to increase polarity that were used in the design of the target compounds could produce the expected selective peripheral distribution, preventing entry into the central nervous system, we evaluated the brain permeability of these compounds by the widely used in vitro parallel artificial membrane permeability assay for blood-brain barrier (BBB) (PAMPA-BBB) [41], using a lipid extract of porcine brain membrane

Summary

Introduction

Myasthenia gravis is an autoimmune disease that is associated with antibodies directed against nicotinic acetylcholine receptors (AChRs) on the postsynaptic membrane at the neuromuscular junction, Molecules 2018, 23, 634; doi:10.3390/molecules23030634 www.mdpi.com/journal/moleculesMolecules 2018, 22, x or against other proteins, as muscle-specific tyrosine kinase with (MuSK), low-densityMyasthenia gravis issuch an autoimmune disease that is associated antibodies directedlipoprotein against receptor-related protein (LRP4), and agrin, which are involved in AChR clustering on the postsynaptic nicotinic acetylcholine receptors (AChRs) on the postsynaptic membrane at the neuromuscular membrane in structural maintenance of muscle-specific the neuromuscular synapseAntibodies against junction, and or against other proteins, such as tyrosine kinase[1,2].AChRs may block these receptors by binding toand the agrin, acetylcholine-binding site,inmay reduce the number lipoprotein receptor-related protein4 (LRP4), which are involved clustering on the postsynaptic membrane and in structural maintenance theactivate neuromuscular synapse cascade, [1,2].of available receptors in the membrane by internalization, andofmay the complementAntibodies against AChRs block these receptors by binding the acetylcholine-binding leading to destruction of the may postsynaptic muscle membrane and,tohence, negatively affectingsite, may reduce number available receptors in the membrane internalization, and may activate function [2,3]. the Failure of of neuromuscular transmission leads tobyfluctuating skeletal muscle fatigue complement cascade, leading to destruction membrane and, andthe weakness upon repeated contraction, whichof is the the postsynaptic main clinicalmuscle hallmark of myasthenia gravis.negatively affecting function [2,3].Failure of neuromuscular transmission leads to Weakness affects various muscle groups, such as extraocular muscles, which control eyefluctuating movements, skeletal muscle and weakness upon repeated contraction, which is the main clinical hallmark bulbar muscles infatigue the mouth and throat, responsible for speech and swallowing, and limb and axial of myasthenia gravis. Myasthenia gravis issuch an autoimmune disease that is associated antibodies directedlipoprotein against receptor-related protein (LRP4), and agrin, which are involved in AChR clustering on the postsynaptic nicotinic acetylcholine receptors (AChRs) on the postsynaptic membrane at the neuromuscular membrane in structural maintenance of muscle-specific the neuromuscular synapse. Antibodies against AChRs block these receptors by binding the acetylcholine-binding leading to destruction of the may postsynaptic muscle membrane and,tohence, negatively affectingsite, may reduce number available receptors in the membrane internalization, and may activate function [2,3]. The Failure of of neuromuscular transmission leads tobyfluctuating skeletal muscle fatigue complement cascade, leading to destruction membrane and, andthe weakness upon repeated contraction, whichof is the the postsynaptic main clinicalmuscle hallmark of myasthenia gravis. Weakness affects various muscle groups, such as extraocular muscles, which muscles [1]

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