Nicotinic acid esters, activity

XXXIII, are active in DOCA rats and in dogs. The nicotinic acid ester H-1 (XXXIV) is a hypotensive and vasodilator in spontaneous hypertensive rats. ... 

A. Salvi, P. A. Carrupt, J. M. Mayer, B. Testa, Esterase-Like Activity of Human Serum Albumin toward Prodrug Esters of Nicotinic Acid , Drug Metab. Dispos. 1997, 25, 395-398. 

The methyl ester of nicotinic acid is selectively reduced to the 1,2-dihydropyridine 166 in a vast improvement over previous methods (Equation 87) <20010L201>. Low temperatures and choice of pyridinium-activating agent are crucial to avoid 1,4-dihydropyridine formation. A modification of Fowler s dihydropyridine synthesis was used to prepare the iV-acyldihydropyridine 167 (Equation 88) <20060L2961>. 

The greatest hazard to life arises from suppression of the ability to secrete sweat, which can give rise to fatal hyperthermia if body temperature is not controlled artificially during hot weather or strenuous activity. Another source of hazard to life arises from the effect of the compounds other than scopolamine and its quaternary form in accelerating heart rate and facilitating Intramural conduction and transmission of Impulses. Ihese actions may result in serious arrhythmias up to and including ventricular fibrillation. The quaternary amine forms of the tropic acid esters in which we are interested are more active in some respects than the tertiary amines, as far as peripheral actions are concerned. This is especially true with respect to actions on nicotinic effectors in ganglia and striated muscles. The quaternary amines penetrate into the central nervous system poorly, but, once there, affect muscarinic effectors in the same way as the tertiary amines. 

These nicotinic acid intermediates were also converted to their corresponding ethyl esters by reaction with ethyl alcohol in the presence of sulfuric acid. Surprisingly, the alkyl amides had some pre- and postemergent herbicidal activity with bleaching symptomology. The activity was quite weak, less than 50% weed control was observed at 2 lb/acre. The esters, on the other hand, were almost devoid of herbicidal activity. 

Nicotinic acid and its reduced form, nicotinyl alcohol, have been used for years in attempts to manage peripheral vascular disease. However, nicotinic acid and the alcohol (which is metabolized to the acid) have weak vasodilating activity. At tolerated doses they probably exhibit some activity on dermal blood vessels. The nitrate ester of N-(p-hydrox-yethyl)nicotinamide, nicorandil, was developed in Japan as an antianginal agent. The drug has coronary and peripheral vasodilating properties as well as spasmolytic effects. It thus acts as a classical nitrate. Whether the molecular mechanisms are the same has not been established. 

Nicotinic acid was first identified as an essential dietary supplement in 1937. It can be found in an active form as either free nicotinic acid, the amide derivative or bound to the pyridine-containing nucleotides (nicotinamide adenine dinucleotide (NAD) and the corresponding phosphate ester (NADP)). 

Lindsey and Maxwell, 1949) phosphoric acid 0.005% (Eckey, 1934, 1935 Kraybill and Beadle, 1948) thiodipropionic acid 0.01% and its esters (O Leary, 1946) and lecithin in any amount (Evans, 1935 Olcott and Mattill, 1936). Many other compounds have been reported to have synergistic activity, including normal constituents of meat such as amino acids (Clausen et cd., 1947), ascorbic acid (Golumbic and Mattill, 1941 Calkins and Matthill, 1944), nicotinic acid (Taub and Simone, 1947), and para-aminobenzoic acid (Norris, 1949). 

Studies of purified plasmin have helped to recognize some of its requirements. The purified enzyme is activated by the addition of nicotinic acid, and the addition of organic phosphate protects the preparation against denaturation. Plasmin can also be protected by arginine-ethylene and lysine-ethylene esters. 

An increase in the duration of activity of nicotinic acid and a diminution in some of its undesirable side effects were partially achieved by esterification with selected alcohols. Upon hydrolysis by esterases the alcohol component could contribute its own therapeutic effect. Thus, acylation of the polyalcohol myoinositol, (mesoinositol) with nicotinic acid afforded the ester (V). Mesoinositol hexanicotinate (V) reduced blood cholesterol levels in the hypercholesterolemic individual but not in normal subjects [57]. In addition, patients with arteriosclerosis obliterans showed an increase in walking ability after oral therapy with mesoinositol hexanicotinate [58]. A considerable portion of the C-labeled ester (V) circulated unchanged in the blood of the cat [59]. 

Sorbitol is another polyalcohol which has been condensed with nicotinic acid to furnish sorbitol hexanicotinate (VI). This ester was found to possess hypolipidemic activity in h5 ercholesterolemic experimental animals [60]. The intramuscular injection of 2-diethylaminoethyl nicotinate (VII) produced a significant reduction in the free fatty acid content of plasma in man [61]. 

Esters of pyridine-carboxylic acids react normally with compounds containing activated methylene groups. The reactions are valuable, for example as routes to acylpyridines. The ethoxide-catalysed condensation of ethyl pyridine carboxylates with ethyl acetate has often been described early work suggested that esters of nicotinic acid gave lower yields than their isomers, but this is not so . Many esters other than ethyl acetate have been used and a number of substituted pyridine esters > Condensations with picolines to give desoxypyridoins are of practical value (p. 380). 

FIGURE 1.9 Records of the minute electrical currents (downward deflections) that flow through single ligandgated ion channels in the junctional region of frog skeletal muscle. The currents arise from brief transitions of individual nicotinic receptors to an active (channel open) state in response to the presence of various agonists (ACh = acetylcholine SubCh = suberyldicholine DecCh = the dicholine ester of decan-1,10-dicarboxylic acid CCh = carbamylcholine). (From Colquhoun, D. and Sakmann, B., J. Physiol., 369,501-557, 1985. With permission.)... 

The hydrazinium nicotinate group on these reagents commonly is protected against reaction with the active ester by the addition of acetone to form the acetone hydrazone derivative. This hydrazone protective group is readily reversible at neutral or mildly acidic pH and will immediately exchange with a benzaldehyde on the corresponding chemoselective partner to form a stable hydrazone linkage. 

Syntheses of naphthyridone derivatives follow the same procedures as those of quinolones, except that substituted 2-aminopyridines (Gould-Jacobs modification) or substituted nicotinic ester/nicotinoyl chloride are used instead of anilines or o-halobenzoic acid derivatives. Most of the recently introduced quinolone antibacterials possess bicyclic or chiral amino moieties at the C-7 position, which result in the formation of enantiomeric mixtures. In general, one of the enantiomers is the active isomer, therefore the stereospecific synthesis and enantiomeric purity of these amino moieties before proceeding to the final step of nucleophilic substitution at the C-7 position of quinolone is of prime importance. The enantiomeric purity of other quinolones such as ofloxacin (a racemic mixture) plays a major role in the improvement of the antibacterial efficacy and pharmacokinetics of these enan-... 

Whereas the above evidence clearly points to a catalytic activity of serum albumin, it does not exclude an activity toward less-reactive substrates due to contamination of some HSA preparations. Indeed, the hypothesis of a contamination by plasma cholinesterase (EC 3.1.1.8) has been raised [126][127]. The efficient hydrolysis of nicotinate esters by HSA (see Chapt. 8) [128][129] could be due to contamination by cholinesterase in samples of a commercially available, essentially fatty acid free albumin. Support for this hypothesis was obtained when HSA contaminated with cholinesterase was resolved into two peaks by affinity chromatography, and the esterase activity toward nicotinate esters was found exclusively in the cholinesterase fraction [130],... 

In contrast to pilocarpine, arecoline acts at nicotinic receptors as well as at muscarinic sites it has been described (172) as a partial agonist at and Mg receptors. Arecoline is equipotent to its quaternary analog, iV-meth-ylarecoline, as a muscarinic agonist (172). The secondary amine, norarecoline, is a somewhat weaker muscarinic agonist than arecoline (173,174). The muscarinic activity of esters of arecaidine (the free carboxylic acid derivative... 

Ester and amide synthesis. Nicotinic anhydride activates carboxyhc acids (by forming mixed anhydrides) to be transformed into esters and amides, with alcohols and amines, respectively (catalytic DMAP). 

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