Choline esters

The choline ester is prepared by treating the 2-bromoethyl ester with trimethyl-amine. The ester is cleaved with butyrylcholine esterase (pH 6, 0.05 M phosphate buffer, rt, 50-95% yield). As with the morpholinoethyl ester, the choline ester imparts greater solubility to the C-terminal end of very hydrophobic peptides, thus improving the ability to cleave enzymatically the C-terminal ester. ... 

ChEs hydrolyze choline esters and carboxylic esters (1, 2 respectively) ... 

In the order Buccinidae (whelks) the salivary glands contain large amounts of tetramine and other small molecular weight substances such as choline esters. However, there is little evidence for their use as toxins according to zoological observations (22). 

Murexine and related compounds have marked actions on the nicotine receptor as expected from choline esters (87-89). Toxins from the digestive glands of nudi-branchs have marked effects on the cardiovascular system of the rat (23). Antiviral and antibacterial substances have been obtained from molluscs (90,91). 

Quaternary amine (or choline ester) Monoamine (a catecholamine) Monamine (a catecholamine) Secondary amine (a catecholamine) Monoamine (an indoleamine) Monoamine (an imidazoleamine)... 

Enzyme Labile Carboxyl Protecting Groups Choline Ester (OCho)... 

Acid- and base-sensitive lipidated peptides can be selectively deprotected by enzymatic hydrolysis of choline esters.[13al Choline esters of simple peptides, but also of sensitive peptide conjugates like phos-phorylated and glycosylated peptides,1141 nucleopep-tides1151 and lipidated peptides,113,1631 can be cleaved with acetyl choline esterase (AChE) and butyryl choline esterase (BChE) under virtually neutral conditions with complete chemoselectivity. Acid-labile farnesyl groups and base-sensitive thioesters are not attacked. 

For instance, in a synthesis of N-Ras lipopeptide 8, the choline ester in the palmitoylated tripeptide 5 was removed selectively and in high yield by means of the butyryl choline esterase (BChE). Efficient cou-... 

Scheme 9. N-Ras peptide synthesis employing choline esters as C-terminal protecting group. EDC 1-ethyl-3 (dimethylamino)propyl-carbodiimide hydrochloride, HOBt 1-hydroxybenzo-tri azole...

The contribution of pseudocholinesterase, also known simply as cholinesterase, to drug metabolism is much greater as it possesses considerably broader substrate selectivity. In addition to acetylcholine, it will hydrolyze other choline esters like the muscle relaxant succinylcholine. It will also hydrolyze non-choline-containing drugs like the local anesthetic procaine and the anti-inflammatory agent aspirin (Fig. 6.5). Cholinesterases, particularly... 

Darvesh S, McDonald RS, Darvesh KV, et al. On the active site for hydrolysis of aryl amides and choline esters by human cholinesterases. Bioorg Med Chem 2006 14(13) 4586 1599. 

Thus a distinction was provided between simple esterases, such as fiver esterase, which catalysed the hydrolysis of simple aliphatic esters but were ineffective towards choline esters. The term 1 cholinesterase was extended to other enzymes, present in blood sera and erythrocytes of other animals, including man, and in nervous tissue, which catalysed the hydrolysis of acetylcholine. It was assumed that only one enzyme was involved until Alles and Hawes2 found that the enzyme present in human erythrocytes readily catalysed the hydrolysis of acetylcholine, but was inactive towards butyrylcholine. Human-serum enzyme, on the other hand, hydrolyses butyrylcholine more rapidly than acetylcholine. The erythrocyte enzyme is sometimes called true cholinesterase, whereas the serum enzyme is sometimes called pseudo-cholinesterase. Stedman,3 however, prefers the names a-cholinesterase for the enzyme more active towards acetylcholine, and / -cholinesterase for the one preferentially hydrolysing butyrylcholine. Enzymes of the first type play a fundamental part in acetylcholine metabolism in vivo. The function of the second type in vivo is obscure. Not everyone agrees with the designation suggested by Stedman. It must also be stressed that enzymes of one type from different species are not always identical in every respect.4 Furthermore,... 

Steryl choline esters (SCEs) found in the samples are listed in Table 2.102. It can be concluded from the data that the method is suitable for the investigation of the fate of chlorophylls in algae [294],... 

Cholinesterase Acylcholine acylhydrolase, butyrylcholinesterase, pseudocholinesterase Choline esters and other esters... 

In contrast to acetylcholinesterase, cholinesterase (acylcholine acyl-hydrolase, butyrylcholinesterase, EC 3.1.1.8) exhibits relatively unspecific esterase activity toward choline esters, with abroad specificity relative to the size of the acyl group. The enzyme is synthesized in the liver and can be found in smooth muscle, adipocytes, and plasma. Its physiological role remains partly obscure, but there is evidence that it is present transiently in the embryonic nervous system, where it is replaced in later stages of development by acetylcholinesterase. It has, therefore, been suggested that cholinesterase functions as an embryonic acetylcholinesterase. 

Peptide 21, synthesized using the C-terminal enzymatic-cleavable choline ester (Scheme 11), was also synthesized using the C-terminal allyl ester protecting group (Scheme 12). The selective Pd(0)-catalyzed... 

C-terminal deprotection was performed using morpholine as an allyl trap, resulting in high yields. The most significant advantage of the allyl group in this peptide synthesis in comparison with the choline ester is that it overcomes the solubility problem encountered in the enzymatic deprotection approach. The deprotection of the allyl ester is performed in organic solvents, in which these lipidated peptide are readily soluble. ... 

It is well established that acetylcholine can be catabolized by both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) these are also known as "true" and "pseudo" cholinesterase, respectively. Such enzymes may be differentiated by their specificity for different choline esters and by their susceptibility to different antagonists. They also differ in their anatomical distribution, with AChE being associated with nervous tissue while BChE is largely found in non-nervous tissue. In the brain there does not seem to be a good correlation between the distribution of cholinergic terminals and the presence of AChE, choline acetyltransferase having been found to be a better marker of such terminals. An assessment of cholinesterase activity can be made by examining red blood cells, which contain only AChE, and plasma. 

The choline ester, carbachol, activates M-cholinoceptors, but is not hydrolyzed by AChE. Carbachol can thus be effectively employed for local application to the eye (glaucoma) and systemic administration (bowel atonia, bladder ato-nia). The alkaloids, pilocarpine (from Pilocarpus jaborandi) and arecoline (from Areca catechu betel nut) also act as direct parasympathomimetics. As tertiary amines, they moreover exert central effects. The central effect of muscarinelike substances consists of an enlivening, mild stimulation that is probably the effect desired in betel chewing, a widespread habit in South Asia. Of this group, only pilocarpine enjoys therapeutic use, which is limited to local application to the eye in glaucoma... 

This enzyme [EC 3.1.1.8] (also known as cholinesterase, pseudocholinesterase, acylcholine acylhydrolase, nonspecific cholinesterase, and benzoylcholinesterase) catalyzes the hydrolysis of an acylcholine to generate choline and a carboxylic acid anion. A variety of choline esters and a few other compounds can serve as substrates. 

Carbachol is a powerful cholinic ester that stimulates both muscarinic and nicotinic receptors, as well as exhibits all of the pharmacological properties of acetylcholine while in addition resulting in vasodilation, a decrease in heart rate, an increase in tone and con-tractability of smooth muscle, stimulation of salivary, ocular, and sweat glands as well as autonomic ganglia and skeletal muscle. For this reason, use of carbachol, like acetylcholine, is limited. The exception is that it is used in ophthalmological practice and post-operational intestines and bladder atony. Upon administration in the eye, the pupil constricts and the intraocular pressure is reduced. It is used for severe chronic glaucoma. Synonyms of this drag are doryl and miostat. 

Atropine (Various) Cholinergic agents Organophosphates, carbamates, pilocarpine, physostigmine, or choline esters. 

Acetylcholine is an ester of choline and acetic acid, the prototype for a small family of choline ester compounds. The choline moiety of ACh contains a quaternary ammonium group that gives ACh a permanent positive charge, making it very hydrophilic and membrane impermeant. 

Pilocarpine is a naturally occurring cholinomimetic alkaloid that is structurally distinct from the choline esters. It is a tertiary amine that crosses membranes relatively easily. Therefore, it is rapidly absorbed by the cornea of the eye, and it can cross the blood-brain barrier. Pilocarpine is a pure muscarinic receptor agonist, and it is unaffected by cholinesterases. Muscarine is an alkaloid with no therapeutic use, but it can produce dangerous cholinomimetic stimulation following ingestion of some types of mushrooms (e.g., Inocybes). 

SA node and A-V fibers become dominant. Activation of M2 receptors increases the potassium permeability and reduces cAMP levels, slowing the rate of depolarization and decreasing the excitability of SA node and A-V fiber cells. This results in marked bradycardia and a slowing of A-V conduction that can override the stimulation of the heart by catecholamines released during sympathetic stimulation. In fact, very high doses of a muscarinic agonist can produce lethal bradycardia and A-V block. Choline esters have relatively minor direct effects on ventricular function, but they can produce negative inotropy of the atria. 

The choice of route of administration plays an important role in the actions of directly acting choli-nomimetics. An adverse effect of choline esters that may be avoided by selection of an appropriate route of administration is ... 

B. Hypotension, which can be fife threatening, can be avoided by preventing the entry of directly acting cholinomimetics into the circulatory system. Bradycardia and sweating are also avoided by the same precaution, but they are less significant. Delirium is not an issue for choline esters, since they do not enter the CNS. 

Brand Name(s) Duvoid, Urecholine Chemical Class Choline ester... 

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