Diamine oxidase inhibitors

BRL 61063 dpamfylline. brocresine [ban, inn. usan) (CL 54998 nsd 1055) is a substituted bromophenol, a HISTIDINE DECARBOXYLASE INHIBITOR and DIAMINE OXIDASE INHIBITOR. It was formerly used in the treatment of gastric ulcers, brodimoprim [inn] is a dihydrofolate reductase INHIBITOR which can be used as an antibacterial and SULPHONAMIDE potentiator. 

DIAMINE OXIDASE INHIBITORS act on the non-selective enzyme diamine oxidase (histaminase), which has as substrate such diverse substances as histamine, cadaverine and putrescine. As with the monoamine-oxidase enzyme, an intermediate complex is formed to yield the aldehyde, and this is then oxidized. The enzyme has been studied in relation to histamine metabolism, and is found to be released in certain circumstances from eosinophils and other tissues, and can be used as a marker in thyroid and ovarian carcinoma. Blood levels are raised in pregnancy, and heparin raises these levels. Amounts of the enzyme are high in the intestinal mucosa, liver and kidney of most species, A preparation of the enzyme itself (Torantil ) was once available for use in therapeutics for conditions in which a deficiency of histamine was implicated. 

The most specific metabolizing enzyme is imidazole N-methyl-transferase ( histamine acetylase ), which can be inhibited in vivo by amodiaquine, chloroquine and metoprine. Histamine is also metabolized by hlstaminase , and this enzyme can be inhibited by aminoguanidine, metronidazole and pentamidine (see diamine oxidase inhibitors). Metabolites in the urine can be measured to give some index of histamine turnover. 

ANTIMICROBIAL with ANTIBACTERIAL and ANTIPROTOZOAL actions. It widely used orally for a range of bacterial and protozoal infections. It acts as a potent aldehyde DEHYDROGENASE INHIBITOR, which can lead to Significant interactions with other drugs. It is also a diamine oxidase INHIBITOR. 

Monoamines as substrates for diamine oxidase. There have been reports in the literature of the oxidation by diamine oxidase preparations of varying degrees of purity, of compounds which previously were recognized as typical substrates for monoamine oxidase only (117-119). The rates of oxidation of the monoamine substrates in these instances were usually lower than those for the diamines. In addition the enzyme preparations showed the expected susceptibility to typical diamine oxidase inhibitors (cyanide, carbonyl reagents, etc.). As a result of such studies it seemed that a new type of amine oxidase had been discovered. The status of this problem is at present unclear. 

A minor route for histamine catabolism involves histamine conversion to imidazoleacetic acid [via diamine oxidase (histaminase)]. In the major route histamine is converted to methylhistamine [via histamine jV-methyl transferase] which is then converted to methylimi-dazoleacetic acid [via MAO]. A large number of MAO inhibitors have been isolated from plants (Table 6.5). 

ANTIFUNGAL, ANTIMICROBIAL and ANTIINFLAMMATORY activity, and to be a powerful cytotoxic agent (functioning by DNA intercalation and uncoupling of oxidative phosphorylation). It is an ENZYME INHIBITOR (alanine aminotransferase and human plasma diamine oxidase). It shows antiplaque activity, and has been used in toothpastes and oral rinses. Causes temporary change in intraocular pressure. Sanomigran pizotifen. 

Lobelanine (242) and lobelanidine (238) blocked nicotine-induced seizures in rats (ED50 = 25 nmole each) [518]. Lobelanidine was found to be a competitive inhibitor of pea diamine oxidase (Ki = 0.36 mM) 242 was inactive [453], Both 242 and 238 were recently synthesized and 238 was found to be a respiratory stimulant [536]. 

Diamine oxidases belong to a widespread class of enzymes related to polyamine metabolism (Hill, 1971 Smith, 1985). Being a key enzyme in the metabolism of polyamines, essential for the growth and replication of all living cells (Bachrach, 1973 Walters, 1987), they catalize the oxidative deamination of a range of primary diamines (Fig. 2) (Equi et ai, 1991). Inhibitors of diamine oxidases are known to possess antimalarial, antitrypanosomal, antibacterial, and antifungal activities together with possible roles in cancer chemotherapy (Equi et ai, 1991). 

Hui, J. Y., and Taylor, S. L. (1985). Inhibition of in vivo histamine metabolism in rats by foodborne and pharmacologic inhibitors of diamine oxidase, histamine iV-methyltransfer-ase and monoamine oxidase. Toxicol. Appl. Pharmacol. 81, 241-249. 

Impromidine is a selective H2 agonist used as a diagnostic aid the potency varies between 9 and 100 times histamine depending on the test system [312, 314,315]. In humans, it produces maximal gastric acid secretion, an effect inhibited by cimetidine [316]. It is a potent inhibitor of histamine methyl transferase and diamine oxidase [315]. The two imidazole units and the... 

Fig. 2. Biogenetic links between A primary metabolism and B the alkaloid-specific pathway. CAP, N-carbamoylputrescine GABA, 4-aminobutyric acid. Inhibitors DFMA, a-difluorome-thylarginine, HEH, /1-hydroxyethylhydrazine. Enzymes 1, arginine decarboxylase 2, agmatine iminohydrolase 3, JV-carbamoylputrescine amidohydrolase 4, diamine oxidase 5, pyrroline dehydrogenase (NAD+-dependent) 6, spermidine synthase 7, a putrescine-producing poly-amine oxidase (H H-insensitive) 8, homospermidine synthase 9, an HEH-sensitive polyamine oxidase...

The animal diamine oxidase is inhibited by cyanide and other carbonyl reagents. In contrast to liver monoamine oxidase, diamine oxidase is not sensitive to p-chloromercuribenzoate or other SH reagents. Iso-nicotinoyl hydrazide is a potent inhibitor of diamine oxidase. The chemical basis for the inhibitions are not known. It has been suggested that the bacterial enzymes contain flavins, but there is no evidence for any cofactors in the animal enzymes. Again in contrast to monoamine oxidase, diamine oxidase is inhibited by excess substrate. This is interpreted as showing combination of the enzyme with separate substrate molecules at the two adsorbing sites in this situation there is no effective reaction, as the catalysis appears to require combination of the substrate at two points. 

---