Nicotinamide antagonists

Pyriminil toxicity occurs primarily because it inhibits NADH ubiquinone oxidoreductase activity of complex I in mammalian mitochondria resulting in preferential toxicity to high-energy-demanding cells such as nerves and pancreatic jS-cells. However, pyriminil may also act as a nicotinamide antagonist and interfere with the synthesis of NADH/NADPH, furthering neural and jS-cell toxicity. Inhibition of mitochondrial respiration in nerves causes somatic, autonomic, and central nervous system neuropathies while inhibition in jS-cell causes an immediate, irreversible insulin-dependent diabetes mellitus condition. Pyriminil also acts as a noncompetitive inhibitor of rat acetylcholinesterase. 

The antagonists of nicotinic acid are 6-aminonicotinamide and, less potent, 3-acetylpyridine and pyridine-3-sulfonic acid (H15, J4). Nicotinamide has also been reported to be effective in experimental cancer (S3). It is supposedly converted to nonphysiological nucleotide analogs of NAD and NADP because it becomes attached to available apo-dehydrogenase the resulting enzyme cannot function in hydrogen and electron-transfer reactions essential to normal cellular metabolism (D7). 

D7. Dietrich, L. S., Friedland, I. M., and Kaplan, L. A., Pyridine nucleotide metabolism mechanism of action of the niacin antagonist, 6-amino-nicotinamide. ]. Biol. Chem. 233, 964-968 (1958). 

Elucidation of the mode of action of RH-787 is still in progress. The action seems to be effected by the formation of a toxic metabolite, which could be a competitive antagonist of nicotinamide in the synthesis of the coenzyme NAD and its phosphate, NADP. Blocking of methaemoglobin has also been observed, resulting in internal haemorrhage. Other symptoms are paralysis of the hind legs and death after respiratory stress. Its antidote is vitamin PP, nicotinamide (Prevot, 1975). 

Azaserine, a glutamine antagonist," is known to inhibit the NAD synthetase reaction in which nicotinic acid adenine dinucleotide is converted into NAD with glutamine or ammonia as the nitrogen donor. ° When azaserine or azaleucine was fed to Ricinus communis plants followed by [6- C]quinolinic acid, a marked decrease in incorporation of radioactivity into ricinine was observed with azaleucine, less so with azaserine." Both azaserine and azaleucine were found also to inhibit the incorporation of [6- " C]quinolinic acid into pyridine nucleotide cycle intermediates [in the case of azaserine the conversion of nicotinic acid dinucleotide into nicotinamide adenine dinucleotide (NAD ) was apparently inhibited]. 

Ray SD, Balasubramanian G, Bagchi D et al. Ca(2+)-calmodulin antagonist chlorpromazine and poiy(ADP-ribose) polymerase modulators 4-aminobenzamide and nicotinamide influence hepatic expression of BCL-XL and P53 and protect against acetaminophen-induced programmed and unprogrammed cell death in mice. Free Radic Biol Med 2001 31(3) 277-91. 

Researchers at Celltech identified a novel series of nicotinamide N-oxides as CXCR2 antagonist [127]. For instance, 6[Pg.291]

It is known that the toxic action of 6-mercaptopurine can be prevented by injection of adenylic acid or by a number of related substances (214)-6-Mercaptopurine has been found to inhibit DPN synthesis in the liver of mice injected with nicotinamide (199). This inhibition can be antagonized by an administration of adenylic add. Similar results have been obtained with another purine antagonist, thioguanine. Both 6-mercaptopurine and thioguanine not only decrease the amount of DPN synthesis but also interfere with the return of the DPN to its normal value at the end of the 24-hr period. The difference at 24 hr for 6-mercaptopurine was found to be as great as fivefold. The effect of the drug on the return to normal levels is not reversed by the introduction of adenylic acid. 

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