Histamine imidazole ring

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 pKa of the imidazole ring is near 6 (16) so histamine would only exist as an ion in the acidic (pH = 2-3) mobile phase. One would predict no retention on a bonded phase column under this condition however, it does occur. Figure 3 is the simplest way to account for this retention. Here, the mineral acid acts as the counter-ion, as well as the buffer. All of the histamine in the mobile phase is in the ionic form and is in equilibrium with the ion-pair which is only soluble in the stationary phase chemically bonded to silica. Histamine only elutes in the ionic form and is then derivatized for detection. A sharp peak in the chromatogram with good shape and no change in retention time with variation in sample concentration indicates a working system. However, if the paired ion has some solubility in the mobile phase, peak tailing occurs. 

Cimetidine contains an imidazole ring comparable to histamine, a sulfur atom (thioether group) in the side-chain, and a terminal functional group based upon a guanidine (see Section 4.5.4). Ranitidine bears considerable similarity to cimetidine, but there are some important differences. The heterocycle is now furan rather than imidazole, and the guanidine has been modified to an amidine (see Section 4.5.4). A newer drug, nizatidine, is a variant on ranitidine with a thiazole heterocyclic ring system. 

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. 

Cimetidine, the first released H2-blocker, like histamine, contains an imidazole ring structure. It is well absorbed following oral administration, with peak blood levels 45 to 90 minutes after drug ingestion. Blood levels remain within therapeutic concentrations for approximately 4 hours after a 300-mg dose. Following oral administration, 50 to 75% of the parent compound is excreted unchanged in the urine the rest appears primarily as the sulfoxide metabolite. 

Solid phase attachment of histidine-containing peptides by anchoring the imidazole ring to trityl resins has been developed for combinatorial library preparation of diketopiperazines <99TL809>. Histidine, histamine, and urocanic acid are edl imidazole-containing molecules that have been attached to a trityl-type resin to allow their application to combinatorial chemistry <99TL2825>. 

Histamine, an important mediator of inflammation, gastric acid secretion and other allergic manifestations, contain an imidazole ring system. Thiamine, an essential vitamin, possesses a quaternized thiazole ring. 

Small substitutions on the imidazole ring of histamine significantly modify the selectivity of the compounds for the histamine receptor subtypes. Some of these are listed in Table 16-1. 

Histidine and histamine derivatives, as well as other imidazoles, have been successfully immobilized by N-tritylation of the imidazole ring with trityl chloride resin [534] (Entry 2, Table 3.29 see also Section 15.8) or with 2-chlorotrityl chloride resin [535-537]. Histidine can also be linked to insoluble supports as the N-dinitrophenyl deriva-... 

Most substituted imidazoles are obtained via the condensation of non-cyclic fragments to form the desired imidazole. The majority of these condensation reactions has recently been reviewed by Grimmett8. The largest number of imidazoles obtained via condensation approaches is only of limited use for the development of histaminergic ligands as they are mainly polysubstituted imidazoles. For the histamine receptors proper substitution of the imidazole ring is usually limited to the 4(5)-position, with the exception of the histamine H]-receptor, where a broader range of substituents on the 2-position is tolerated. 

Additional substitution of the imidazole of histamine is not tolerated by the H3 receptor, too. Thus, methylation of histamine in either position of the imidazole ring... 

Furthermore, due to its structural similarity to histamine (R)-a-methylhistamine (12) shows high affinity for histamine methyltransferase (HMT). Accordingly, methylation of the imidazole ring by HMT accounts for the short plasma half-life of (/ )-a-methylhistamine (12) in man (tVl = 3 min) [6], It is assumed that the primary amine functionality of the side chain plays a key role in the interaction between... 

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). 

The development of rigid histamine analogues is important for the determination of the H3 receptor pharmacophore as the conformations of these compounds only allow restricted spatial orientation of the imidazole ring with respect to the basic nitrogen in the side... 

The imidazole ring occurs naturally in histamine 3.5, an important mediator of inflammation and gastric acid secretion. A quaternised thiazole ring is found in the essential vitamin thiamin 3.6. There are few naturally occurring oxazoles, apart from some secondary metabolites from plant and fungal sources. 

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