Amine choline

The transport of amino acids at the BBB differs depending on their chemical class and the dual function of some amino acids as nutrients and neurotransmitters. Essential large neutral amino acids are shuttled into the brain by facilitated transport via the large neutral amino acid transporter (LAT) system [29] and display rapid equilibration between plasma and brain concentrations on a minute time scale. The LAT-system at the BBB shows a much lower Km for its substrates compared to the analogous L-system of peripheral tissues and its mRNA is highly expressed in brain endothelial cells (100-fold abundance compared to other tissues). Cationic amino acids are taken up into the brain by a different facilitative transporter, designated as the y system, which is present on the luminal and abluminal endothelial membrane. In contrast, active Na -dependent transporters for small neutral amino acids (A-system ASC-system) and cationic amino acids (B° system), appear to be confined to the abluminal surface and may be involved in removal of amino acids from brain extracellular fluid [30]. Carrier-mediated BBB transport includes monocarboxylic acids (pyruvate), amines (choline), nucleosides (adenosine), purine bases (adenine), panthotenate, thiamine, and thyroid hormones (T3), with a representative substrate given in parentheses [31]. 

N.A. Amine choline, acetylcholine, bursine, histamine, flavonoids, polypeptides, tyramine.99,102 Control internal bleeding, profuse menstruation. 

Further esterification of the phosphoric acid part with a low-molecular-weight alcohol—most commonly, ethanol-amine, choline, serine, or inositol—gives a phospholipid. 

Coenzyme A is the coenzyme carrier of non-enzyme-bound acyl groups and participates in a wide variety of reactions. Among the types of acceptor molecules which are acylated with displacement of CoA are aryl-amines, choline, imidazole, orthophosphate, dihydrolipoate, andouble bond with different acceptors without displacement of the CoA. (See reference 15.)... 

QuaterniZation. Choline chloride [67-48-1] was prepared ia nearly quantitative yield by the reaction of trimethylamine [121-44-8] with ethylene chlorohydrin at 90—105°C and 981—1471 kPa (10—15 kg/cm ) pressure (44). Precursors to quaternary ammonium amphoteric surfactants have been made by reaction of ethylene chlorohydrin with tertiary amines containing a long chain fatty acid group (45). 

Choline base [123-41 -17, [(CH2)3NCH2CH20H] 0H, triniethyl(2-hydroxyethyl)-ammonium hydroxide, derives its name from bile (Greek chole from which it was first obtained. This so-called free-ch oline is a colorless, hygroscopic Hquid with an odor of trimethyl amine. The quaternary ammonium compound (1) choline [62-49-7] or a precursor is needed in the diet as a constituent of certain phosphoHpids universally present in protoplasm. 

Choline is not usually encountered as the free base but as a salt, most commonly, the chloride, [(CH2)3N(CH2CH20H)] C1 . As a quaternary ammonium hydroxide, choline reacts with hydrochloric acid to form the chloride and water, whereas primary, secondary, and tertiary amines combine with hydrochloric acid to form hydrochlorides. 

An earlier procedure for the production of choline and its salts from natural sources, such as the hydrolysis of lecithin (23), has no present-day apphcation. Choline is made from the reaction of trimethyl amine with ethylene oxide [75-21-8] or ethylene chlorohydrin [107-07-5J. 

The chlorohydrin process (24) has been used for the preparation of acetyl-P-alkylcholine chloride (25). The preparation of salts may be carried out mote economically by the neutralization of choline produced by the chlorohydrin synthesis. A modification produces choline carbonate as an intermediate that is converted to the desired salt (26). The most practical production procedure is that in which 300 parts of a 20% solution of trimethyl amine is neutralized with 100 parts of concentrated hydrochloric acid, and the solution is treated for 3 h with 50 parts of ethylene oxide under pressure at 60°C (27). 

Choline Chloride. This compound [67-48-17 is a crystalline dehquescent salt, usually with a slight odor of trimethyl amine (6). It is very soluble in water, freely soluble in alcohol, slightly soluble in acetone and chloroform, and practically insoluble in ether, benzene, and ligroin. Its aqueous solutions ate neutral to litmus and are stable (4). The specific gravity of these solutions is a straight-line function between pure water and the value of 1.10 for the 80% solution, which represents the approximate limit of solubiUty. Choline chloride absorbs moisture from the atmosphere at relative humidities greater than 20% at 25.5°C. 

Phosphatidylethanolamine synthesis begins with phosphorylation of ethanol-amine to form phosphoethanolamine (Figure 25.19). The next reaction involves transfer of a cytidylyl group from CTP to form CDP-ethanolamine and pyrophosphate. As always, PP, hydrolysis drives this reaction forward. A specific phosphoethanolamine transferase then links phosphoethanolamine to the diacylglycerol backbone. Biosynthesis of phosphatidylcholine is entirely analogous because animals synthesize it directly. All of the choline utilized in this pathway must be acquired from the diet. Yeast, certain bacteria, and animal livers, however, can convert phosphatidylethanolamine to phosphatidylcholine by methylation reactions involving S-adenosylmethionine (see Chapter 26). 

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. ... 

Ethanol and choline glycerolipids were isolated from calf brain and beef heart lipids by PTLC using silica gel H plates. Pure ethanol amine and choline plasmalogens were obtained with a yield of 80% [74]. Four phosphohpid components in the purple membrane (Bacteriorhodopsin) of Halobacterium halobium were isolated and identified by PTLC. Separated phosphohpids were add-hydrolyzed and further analyzed by GC. Silica gel G pates were used to fractionate alkylglycerol according to the number of carbon atoms in the aliphatic moiety [24]. Sterol esters, wax esters, free sterols, and polar lipids in dogskin hpids were separated by PTLC. The fatty acid composition of each group was determined by GC. 

Hepatic steatosis usually is a result of excessive administration of carbohydrates and/or lipids, but deficiencies of carnitine, choline, and essential fatty acids also may contribute. Hepatic steatosis can be minimized or reversed by avoiding overfeeding, especially from dextrose and lipids.35,38 Carnitine is an important amine that transports long-chain triglycerides into the mitochondria for oxidation, but carnitine deficiency in adults is extremely rare and is mostly a problem in premature infants and patients receiving chronic dialysis. Choline is an essential amine required for synthesis of cell membrane components such as phospholipids. Although a true choline deficiency is rare, preliminary studies of choline supplementation to adult patients PN caused reversal of steatosis. 

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

Special mention should be made of the ready conversion of the chlorhydrin, by means of tnmethylamine, to choline, a substance of great physiological importance. Choline chloride is obtained very easily when equimolecular amounts of the two components are made to interact for some time under the influence of heat a concentrated solution of the amine in absolute alcohol is used. 

Two of these systems were studied as models—the acetylation of choline in brain to give acetyl choline (Hebb, Nachmansohn), and of sulfanilamide (the active component in prontosil, Chapter 3) in liver (Lipmann). Sulfanilamide is rapidly inactivated by acetylation on the p-amino group and then excreted. Sulfanilamide is easily diazotized the diazonium salt formed can be coupled with N-( 1 -naphthyl)ethylenedi-amine dihydrochloride to give a pink derivative (Bratton and Marshall, 1939). This formed the basis for an elegant colorimetric assay. Only the free p-amino group reacts, so that as acetylation proceeded color formation diminished. 

Another ion chromatography pharmaceutical application is the analysis of amines and amphoteric compounds such as choline (see Figure 19). Such compounds may be present either as counterions, as mentioned above, or as synthesis by-products. In either case, ion chromatography can be advantageously utilized for this class of compounds due to the limited utility of gas chromatography and the lack of a UV chromophore for such compounds. Again, screening for such compounds in pharmaceutical preparations can be best accomplished... 

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 catalyzes the reaction of a phospholipid (for example, phosphatidylserine) with ethanolamine to produce phosphatidylethanolamine and the free base (/.c., the amine-containing metabolite serine), thereby preserving the phosphodiester linkage. Ethanolamine can be replaced with serine, choline, monomethyletha-nolamine, and dimethylethanolamine. 

This enzyme [EC 3.1.4.39], also known as alkylglycero-phosphoethanolamine phosphodiesterase, catalyzes the hydrolysis of l-alkyl-sn-glycero-3-phosphoethanolamine to produce 1-alkyl-xn-glycerol 3-phosphate and ethanol-amine. The enzyme will also act on the acyl and choline analogs of the lipid. 

ALKENYLGLYCEROPHOSPHOETHANOL-AMINE HYDROLASE 1-ALKYL-2-ACETYLGLYCEROL CHOLINE PHOSPHOTRANSFERASE 1-ALKYL-2-ACETYLG LYCEROPHOSPHO-CHOLINE ESTERASE Alkylation,... 

The mechanism of action of neuroleptics is not sufficiently clear. However, it is believed that they are antagonists of dopamine and dopaminomimetics, and that their effect is connected in some way with the blockage of dopamine D receptors, which results in changes of behavioral reactions. Moreover, it is possible that they also block action on the serotonin receptors and M-choline receptors. It also is possible that antipsychotic agents disrupt the process of the release and return neuronal uptake of a number of biogenic amines. 

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). 

Benzoylcholine chloride has been prepared by heating choline chloride with benzoyl chloride " and by the action of trimethyl-amine on 2-chloroethyl benzoate. ... 

EGb inhibits the uptake of [3H]norepinephrine ([3H]NE) and [3H]dopamine and [3H]5-hydroxytryptamine ([3H]5-HT) into in vitro synaptosomes prepared from the striatum and cortex in a concentration-dependent manner. The rank order of potency for the inhibition of amine uptake is NE > dopamine > 5-HT [173]. Similar results were obtained by Ramassamy et al. [174]. These workers showed that EGb decreased the specific uptakes of [3H]dopamine, [3H]5-HT and [3H]choline by synaptosomes prepared from the striatum of mice in a concentration-dependent manner. The IC,0 values were 637 pg/rol for [3H]dopamine uptake, 803 pg/ml for [3H]5-HT uptake, >2000 pg/ml for [3H]choline uptake. However, they concluded that the inhibition of amine uptake caused by EGb appears to be non-specific, since EGb also prevents the specific binding of the dopamine uptake inhibitor [3H]GBR12783 to membranes prepared from striatum. 

Quarternization of tertiary amines causes jl and y effects which overlap with the shieldings induced by the positively charged nitrogen, as shown for some tetraalkylam-monium salts in Table 4.42 [339], Tetraalkylammonium ions display triplet splittings of 4 Hz due to 13C—14N coupling (/i[Pg.238]

A simple method of modifying promoiety acidity or basicity is to select other more acidic or basic ionizable functional groups. Convenient solubilizing moieties for ester prodrugs where the formulation pH should be between 3.5 and 5 would be those containing eithersulfonicKypid or tertiary amine ( ia > 8) functionalities. Quaternary ammonium-containing moieties, such as the choline esters mentioned earlier, would also be excellent choices for water-soluble derivatives if solubility was the only consideration (Anderson and Conradi, 1987). 

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