Acetyl-histamins

An alternative pathway of histamine metabolism involves oxidative deamination by the enzyme diamine oxidase (histaminase) to form 5-imidazoleacetic acid. Diamine oxidase is present in both tissues and blood and plays a particular role in metabolizing the large concentrations of histamine that may be present in food. An additional metabolite, A-acetyl histamine (a conjugate of acetic acid and histamine), can be produced if histamine is ingested orally. This product may result from metabolism of histamine by gastrointestinal tract bacteria. Because of its rapid breakdown after oral administration, histamine produces few systemic effects when given by this route. 

Leptodactylus pentadactylus and L. ocellatus native to South and Central America, contain considerable amounts of 5-hydroxytryptamine derivatives, like N-methylserotonine, bufotenin and bufotenidin as well as leptodactylin and candicin (ref. 4). Of a new type are substances like histamin, methyl-, and acetyl-histamins, and spinaceamin. Spinaceamin can be synthesized in vitro by a biomimetic reaction of histamin and formaldehyde in aqueous solution at pH 6.8, and room temperature (ref. 5). 

In addition, Pfister and coworkers investigated 3-hydroxyflavone-6-carboxylic acids as histamine induced gastric secretion inhibitors. After condensing 3-acetyl-4-hydroxybenzoic acid (45) with a variety of aldehydes 46 to deliver the chalcones 47, these purified chalcones were then subjected to the standard AFO conditions to afford flavonols 48 in 51-80% yield. Subsequent alkylation of 48 with methyl iodide or isopropyl iodide followed by saponification of the corresponding esters gave the target compounds. 

Another antiulcer histamine Hj receptor antagonist containing a thiazole moiety is zalb-dine (131) Its synthesis can be accomplished readily by brominating 4 acetyl 2 methylimidazole (129) to give haloketone 130 Displacement with amidinothiourea completes the synthesis of zaltidme (131) via a displacement cyclodehydration sequence [45]... 

G-protein coupled receptor family comprises most well-known cell surface receptors including the major drug targets, as previously stated. Early PAL results have been reviewed in several papers, and book chapters. For opiate, NMDA, sigma, benzodiazepine, GABA, acetyl choline, and adrenerg, serotonine receptors see [52,59,60], and for purinerg, histamine, and dopamine receptors see [61]. 

Fig. 9.8 Examples of rule-of-three compliant molecules that have biological activity better than 10 nM. Under each molecule, the following information is included molecule name, MW, ClogP, the biological activity type, value and target. Target names are as follows D3 and D4 - dopaminergic receptor types 2 and 3 AChE and BChE - acetyl- and butyryl-choline esterases PRa and PRb - progesterone receptor types A and B H] and H3, histamine receptor types 1 and 3 5-HT2a, 5-HT2b, 5-HT2c, 5-HT3, 5-HT4 - serotonin receptor subtypes 2A, 2B, 2C, and types 3 and 4 DAT, NET, 5-HTT - dopamine, norepinephrine and serotonin transporter proteins /X], /x.2, S, ki, ks - opioid receptor types mu-1, mu-2, delta, kappa-1 and kappa-3 5a-Rl and 5o -R2 - 5-alpha-reductase isozymes 1 and 2 Flt-1-fms-like tyrosine kinase receptor.

Histamine is rapidly degraded by oxidative de-samination by the diaminooxidase histaminase, acetylation of the NH2-group, methylation of the ring and oxidation of the methylhistamines by the mono-aminoxidase. The main metabolites are the N-methyl-imidazole acetic acid and the imidazole acetic acid. Histamine interacts with at least four different specific receptors Hi to H4 (see Table 1). 

The acetylation of some primary aliphatic amines such as histamine. mescaline. and the bis-N-demethylated metabolite of of-j-methadol" "" also has been reported. In comparison with oxidative deamination processes. N-acetylation is only a minor pathway in the metabolism of this cla.ss of compounds. 

Figure 4-16 a Examples of H different types of compound undergoing N-acetylation. Arrow indicate sites of N-acetyla- Histamine... 

It is believed that the weight gain observed in patients being administered typical antipsychotics is related to the antagonist action of these drugs at acetyl choline, serotonin and histamine-1 receptors. 

In 1911 he was the first to identify the compound histamine in animal tissues, and he studied its physiological effects, concluding that it was responsible for some allergic and anaphylactic reactions. After successfully isolating acetylcholine in 1914, he established that it was found in animal tissue, and in the 1930s he showed that it is released at nerve endings in the parasympathetic nervous system, establishing acetyl-... 

Chromone derivatives, in particular 2-spiro-chroman-4(lF/)-ones, are ubiquitous in nature and possess various biological activities which include antiarrhythmic, anti-HIV, antidiabetic, acetyl-CoA carboxylase (ACC) inhibitor, vanilloid receptor antagonist, growth hormone secretagogues, histamine receptor antagonist, and... 

Fig. 13. Separation of amines including histamine and iV-dimethylhistainine as acetyl derivatives at 198°C with an F-60-Z phase /8HO-PE = jS-hydroxyphenyl-ethylamine ME-HIST = iV-dimethyUiistamine TYR = tyramine HIST = histamine 3-MeO-TYR = 3-methoxytyramine OCTOP = octopamine TRYPT = tryptamine MET = metanephrine NORMET = nonnetanephrine. Reproduced from Brooks and Homing (B24) with permission.

Figure 10,5 (a) logCk J versus pK plots at different temperatures for the hydrogen exchange reaction at the C-2 position of four different Imidazoles Including 1, histamine 2, N -acetyl-L-hlstldlne methyla-mide (Ac-Hls-NHMe) 3, N -acetyl-DL-hlstldine (Ac-Hls-OH) 4, 1 H-lmldazole-5-propanolc acid (IPA). (b) The relationship between the y-Intercepts of the plots In (a) and temperature. The correlation observed for the y-intercepts at a pK of 7.0 Is shown in (b). Reproduced with permission from Ref [28]. 2012, American Chemical Society... 

---