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Cholinesterase Inhibitors/chemical synthesis*

T1 - Multifunctional cholinesterase and amyloid beta fibrillization modulators. Synthesis and biological investigation

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Synthesis, transport, and fate of acetylcholinesterase …

The N-monophenylcarbamate analogues of neostigmine methyl sulfate (6) and pyridostigmine bromide (8) together with their precursors (5), (7), and the N(1)-methylammonium analogues of (-)-phenserine (12), (-)-tolserine (14), (-)-cymserine (16) and (-)-phenethylcymserine (18) were synthesized to produce long-acting peripheral inhibitors of acetylcholinesterase or butyrylcholinesterase. Evaluation of their cholinesterase inhibition against human enzyme ex vivo demonstrated that, whereas compounds 5-8 possessed only marginal activity, 12, 14, 16 and 18 proved to be potent anticholinesterases. An extended duration of cholinesterase inhibition was determined in rodent, making them of potential interest as long-acting agents for myasthenia gravis.

Synthesis and inhibitory activities toward acetylcholine- and butyrylcholinesterases

The carboxyl-terminal cholinesterase-like (ChEL) domain of thyroglobulin (Tg) has been identified as critically important in Tg export from the endoplasmic reticulum. In a number of human kindreds suffering from congenital hypothyroidism, and in the cog congenital goiter mouse and rdw rat dwarf models, thyroid hormone synthesis is inhibited because of mutations in the ChEL domain that block protein export from the endoplasmic reticulum. We hypothesize that Tg forms homodimers through noncovalent interactions involving two predicted α-helices in each ChEL domain that are homologous to the dimerization helices of acetylcholinesterase. This has been explored through selective epitope tagging of dimerization partners and by inserting an extra, unpaired Cys residue to create an opportunity for intermolecular disulfide pairing. We show that the ChEL domain is necessary and sufficient for Tg dimerization; specifically, the isolated ChEL domain can dimerize with full-length Tg or with itself. Insertion of an N-linked glycan into the putative upstream dimerization helix inhibits homodimerization of the isolated ChEL domain. However, interestingly, co-expression of upstream Tg domains, either in cis or in trans, overrides the dimerization defect of such a mutant. Thus, although the ChEL domain provides a nidus for Tg dimerization, interactions of upstream Tg regions with the ChEL domain actively stabilizes the Tg dimer complex for intracellular transport.

Acetylcholinesterase - Wikipedia

T1 - The cholinesterase-like domain, essential in thyroglobulin trafficking for thyroid hormone synthesis, is required for protein dimerization

Accumulating evidence supports the view that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) can influence the proliferation and differentiation of nerve cells. AChE in particular has been found to promote neurite outgrowth in a variety of model systems, possibly by serving as an adhesion molecule. Thus one might suspect that cholinesterase inhibitors would disturb neuronal development, with long-term implications for structure and function in the central and peripheral nervous systems. The actual picture is more complex because AChE's effects on neurite outgrowth may reflect protein-protein interactions that are not directly related to catalytic function but are nonetheless influenced by ligands with special structural features. The putative structural interactions have not yet been rigorously defined, but they are likely to involve enzyme regions at or near the peripheral anionic site. In addition to such effects, some organophosphorus anticholinesterases have been reported to act by still other mechanisms to depress macromolecule synthesis and cell survival in the developing brain. Taken together, this emerging information highlights the potential importance of anticholinesterase agents in developmental neurotoxicology.

Genetic analysis may demonstrate a number of allelic mutations in the pseudocholinesterase gene, including point mutations resulting in abnormal enzyme structure and function and frameshift or stop codon mutations resulting in absent enzyme synthesis. Partial deficiencies in inherited pseudocholinesterase enzyme activity may be clinically insignificant unless accompanied by a concomitant acquired cause of pseudocholinesterase deficiency. Clinically significant effects are generally not observed until the plasma cholinesterase activity is reduced to less than 75% of normal.[2] Pseudocholinesterase deficiency is most common in people of European descent; it is rare in Asians.

cholinesterase explanation free

N2 - Accumulating evidence supports the view that acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) can influence the proliferation and differentiation of nerve cells. AChE in particular has been found to promote neurite outgrowth in a variety of model systems, possibly by serving as an adhesion molecule. Thus one might suspect that cholinesterase inhibitors would disturb neuronal development, with long-term implications for structure and function in the central and peripheral nervous systems. The actual picture is more complex because AChE's effects on neurite outgrowth may reflect protein-protein interactions that are not directly related to catalytic function but are nonetheless influenced by ligands with special structural features. The putative structural interactions have not yet been rigorously defined, but they are likely to involve enzyme regions at or near the peripheral anionic site. In addition to such effects, some organophosphorus anticholinesterases have been reported to act by still other mechanisms to depress macromolecule synthesis and cell survival in the developing brain. Taken together, this emerging information highlights the potential importance of anticholinesterase agents in developmental neurotoxicology.

A personal or family history of an adverse drug reaction to one of the choline ester compounds, such as succinylcholine, mivacurium, or cocaine, may be the only clue suggesting pseudocholinesterase deficiency. Most clinically significant causes of pseudocholinesterase deficiency are due to one or more inherited abnormal alleles that code for the synthesis of the enzyme.

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  • Acetylcholine and Cholinesterase - Reviews - Page 2

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    Design, synthesis and biological evaluation of tacrine-1,2,3-triazole derivatives as potent cholinesterase inhibitors

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Natural Products as Sources of New Drugs over the …

AB - The carboxyl-terminal cholinesterase-like (ChEL) domain of thyroglobulin (Tg) has been identified as critically important in Tg export from the endoplasmic reticulum. In a number of human kindreds suffering from congenital hypothyroidism, and in the cog congenital goiter mouse and rdw rat dwarf models, thyroid hormone synthesis is inhibited because of mutations in the ChEL domain that block protein export from the endoplasmic reticulum. We hypothesize that Tg forms homodimers through noncovalent interactions involving two predicted α-helices in each ChEL domain that are homologous to the dimerization helices of acetylcholinesterase. This has been explored through selective epitope tagging of dimerization partners and by inserting an extra, unpaired Cys residue to create an opportunity for intermolecular disulfide pairing. We show that the ChEL domain is necessary and sufficient for Tg dimerization; specifically, the isolated ChEL domain can dimerize with full-length Tg or with itself. Insertion of an N-linked glycan into the putative upstream dimerization helix inhibits homodimerization of the isolated ChEL domain. However, interestingly, co-expression of upstream Tg domains, either in cis or in trans, overrides the dimerization defect of such a mutant. Thus, although the ChEL domain provides a nidus for Tg dimerization, interactions of upstream Tg regions with the ChEL domain actively stabilizes the Tg dimer complex for intracellular transport.

Chapter 27 - Biological Monitoring

AB - The N-monophenylcarbamate analogues of neostigmine methyl sulfate (6) and pyridostigmine bromide (8) together with their precursors (5), (7), and the N(1)-methylammonium analogues of (-)-phenserine (12), (-)-tolserine (14), (-)-cymserine (16) and (-)-phenethylcymserine (18) were synthesized to produce long-acting peripheral inhibitors of acetylcholinesterase or butyrylcholinesterase. Evaluation of their cholinesterase inhibition against human enzyme ex vivo demonstrated that, whereas compounds 5-8 possessed only marginal activity, 12, 14, 16 and 18 proved to be potent anticholinesterases. An extended duration of cholinesterase inhibition was determined in rodent, making them of potential interest as long-acting agents for myasthenia gravis.

Chapter 27 - Biological Monitoring GENERAL PRINCIPLES

N2 - The N-monophenylcarbamate analogues of neostigmine methyl sulfate (6) and pyridostigmine bromide (8) together with their precursors (5), (7), and the N(1)-methylammonium analogues of (-)-phenserine (12), (-)-tolserine (14), (-)-cymserine (16) and (-)-phenethylcymserine (18) were synthesized to produce long-acting peripheral inhibitors of acetylcholinesterase or butyrylcholinesterase. Evaluation of their cholinesterase inhibition against human enzyme ex vivo demonstrated that, whereas compounds 5-8 possessed only marginal activity, 12, 14, 16 and 18 proved to be potent anticholinesterases. An extended duration of cholinesterase inhibition was determined in rodent, making them of potential interest as long-acting agents for myasthenia gravis.

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