Imidazole-ethylamine

Histamine (2-[4-imidazole] ethylamine) is a low-molecular-weight amine synthesized from L-histidine exclusively by histidine decarboxylase. It is produced by various cells throughout the body, including central nervous system neurons, gastric mucosa parietal cells, mast cells, basophils and lymphocytes [1-4]. Since its discovery as a uterine... 

Table 6 Total energies in a. u. of imidazole, ethylamine, substituted derivatives of both compounds, thiazole, and 2-aminolhiazole...

ReceptorAg onists. In the histamine molecule there are two principal stmctural elements an imidazole moiety and an ethylamine side chain (16). Only the N -position is absolutely necessary for agonism. The imidazole ring can be replaced, eg, 2-pyridylethylamine,... 

The chemical structure of histamine has similarities to the structures of other biogenic amines, but important differences also exist. Chemically, histamine is 2-(4-imidazolyl)ethylamine (Fig. 14-1). The ethylamine backbone is a common feature of many of the amine transmitters (e.g. dopamine, norepinephrine and serotonin). However, the imidazole nucleus, absent from other known transmitters, endows histamine with several distinct chemical properties. Among these is prototypic tautomerism, a property that permits it to exist in two different chemical forms (Fig. 14-1). The tautomeric properties of histamine are thought to be critical in the... 

The Hi-receptor antagonists for the most part are substituted ethylamine compounds. In comparison with histamine, the Hi-antagonists contain no imidazole ring and have substituents on the side chain amino group. 

There is general consensus on the fact that the endogenous agonist histamine, 2-(imidazole-4-yl)ethylamine, binds to the receptor in its monocationic state (protonated at the side chain amine group). The monocationic form is predominantly (96.6%) present at pH 7.4 [11]. In this state, the neutral imidazole ring can exist in two different tautomeric forms, denominated by proximal (it) and tele (x), respectively (Figure 1). 

An interesting observation in our structure-activity studies was that ethylamine, a part of the histamine molecule, 4-(2-ethylamine)imidazole, known for a long time to be a potent stimulator of gastric secretion, also produced duodenal ulcers in rats (20,22). Furthermore, structural similarities also exist between dopamine and histamine H receptor antagonists metiamide and cimetidine (23,24). 

The imidazol coordinates were taken from an x-ray diffraction crystallographic study of histamine (24) with a proton being substituted for the ethylamine side chain of histamine. The coordinates of other reactants, products, and intermediate complexes were calculated employing idealized hybridization and average bond distances or are as discussed. 

Potent agonists for the Hg receptor are obtained by simple modifications of the histamine molecule. The imidazole ring is very important for Hg agonistic activity [17]. Methylation of one of the nitrogens or replacements with other aromatic ring systems are not tolerated [22]. In contrast, subtle changes of the ethylamine side chain have proven to be very usefiil [17]. 

Histamine [2-(imidazol-4-yl)ethylamine] was synthesized and its effects in model biological systems were studied before it was found physiologically. Its synthesis occurs in many tissues, including mast cells, parietal cells of the gastric mucosa, and neurons of the central nervous system (CNS) and the periphery. Early hypotheses about its physiological function were based on the observed, dramatic effects of histamine in guinea pigs. These effects... 

Total energies of the neutral and protonated imidazole (13), 2-methylimidazole (14), 4-methylimidazole (15)l 4-chloroimidazole (16)Fl,4-nitroimidazole (17) l, ethylamine (18), Na-methyl-ethylamine (19), Na,Na-dimethyl-ethylamine (20), thiazole (21), and 2-aminothiazole (22) were also calculated at the same level than previous molecules, and they are presented in Table 6. Tautomers for 15-17 are considered N(s)-H. 

The standard nomenclature for histamine is 1 //-imidazole4(5)-ethanamine. Nevertheless, (2-aminoethyl)-imidazole and /3-(4-imidazolyl)ethylamine are also used in the biological and theoretical studies. In this paper and in all tautomers/ conformers, the ethylamine group is always in position 5 in the imidazolyl group. 

Dimethyl ethanolamine Dimethyl lauramine Dimethyl palmitamine Dimethyl stearamine N,N-Dimethyl-p-toluidine Dipropylenetriamine Dodecenylsuccinic anhydride 2-Dodecen-1-ylsuccinic anhydride Ethylamine Ethylenediamine 2-Ethyl-4-methyl imidazole Hexadecenyl succinic anhydride Hexamethylenediamine Imidazole 1,8-p-Menthanediamine Methyidiethanolamine 4,4 -Methylenedianiline Methyl hexahydrophthalic anhydride Methyl himic anhydride 2-Methyl imidazole 2-Methylpentamethylenediamine 3-Methylpiperidine Nonenyl succinic anhydride Octadecenyl succinic anhydride Octenylsuccinic anhydride N-Oleyl-1,3-propanediamine... 

Histamine (2-(imidazol-4-yl)ethylamine) is one of the most intensely studied molecules in all biological systems. This fact, and its appar-... 

Scheme 9.119. The formation of N-ethylethanonamide (N-ethylacetamide) by reaction of acetic acid with N-ethylamine in the presence of cyclohexylcarbodiimide (top) and carbon-yldiimidazole (bottom). In the first case, dicyclohexylurea is formed along with the amide in the second case, the amide is accompanied by carbon dioxide and two equivalents of imidazole.

---