Histamine synthesis in the

Histamine synthesis in the brain is controlled by the availability of L-histidine and the activity of histidine decarboxylase 254 Histamine is stored within and released from neurons but a neuronal transporter for histamine has not been found 254 In the vertebrate brain, histamine metabolism occurs predominately by methylation 254... 

Histamine synthesis in the brain is controlled by the availability of L-histidine and the activity of histidine decarboxylase. Although histamine is present in plasma, it does not penetrate the blood-brain barrier, such that histamine concentrations in the brain must be maintained by synthesis. With a value of 0.1 mmol/1 for L-histidine under physiological conditions, HDC is not saturated by histidine concentrations in the brain, an observation that explains the effectiveness of large systemic doses of this amino acid in raising the concentrations of histamine in the brain. The essential amino acid L-histidine is transported into the brain by a saturable, energy-dependent mechanism [5]. Subcellular fractionation studies show HDC to be localized in cytoplasmic fractions of isolated nerve terminals, i.e. synaptosomes. 

Hydrocortisone exhibits anti-shock, anti-allergy, and anti-inflammatory action. It raises sugar content in the blood, increases potassium secretion, and lowers sodium excretion from the body. It exhibits anti-metaboUc action and reduces histamine synthesis in the body. 

In more modern times, the first successful anti-ulcer drug, cimetidine 3, with its ability to block histamine synthesis in the stomach, is an imidazole and the classical anti-depressant valium 4 has a seven-membered ring heterocycle that is not (quite) aromatic. 

Levine, R. J., Sato, T. L., and Sjoerdsma, A., 1965, Inhibition of histamine synthesis in the rat by a-hydrazino analog of histidine and 4-bromo-3-hydroxy benzyloxyamine, Biochem. Pharmacol. 14 139-149. 

Mooney RD, Shi MY, Rhoades RW (1994) Modulation of retinotectal transmission by presynaptic 5-HTib receptors in the superior colliculus of the adult hamster. J Neurophysiol 72 3-13 Moreno-Delgado D, Torrent A, Gomez-Ramirez J, de Esch I, Blanco I, Ortiz J (2006) Constitutive activity of H3 autoreceptors modulates histamine synthesis in rat brain through the cAMP/PKA pathway. Neuropharmacology 51 517-23... 

Episodes of airway obstruction or bronchoconstriction may be induced in asthmatics by exposure to stimuli to which they are sensitized, such as inhalation of a specific pollen or house dust mite, or exposure to an occupational stimulus, e.g., red cedar dust [47]. Binding of antigen (e.g., pollen) to specific receptors (antibodies) on the surface of an inflammatory cell (e.g., mast cell) results in the elaboration of prestored mediators, such as histamine, and in the synthesis of newly formed mediators, such as arachidonic acid metabolites (e.g., prostaglandins and leukotrienes). Cellular sources of the various mediators are shown in Table 3. Cytokines and chemokines are proteins that participate in pulmonary immune and inflammatory responses. While important, these have not been subjected to discussion in this chapter because these fields are changing very... 

In Chapter 1, the structure, synthesis and toxicity of ricin, a protein present in the endosperm cells of the seeds of the castor oil plant, are described and possible uses of this toxic agent in immunology as conjugates with antibodies are discussed. The biochemical and pharmacological evidence for the presence of functional histamine receptors in the mammalian central nervous system is set out in Chapter 2. Chapter 3 covers the chemical properties of molybdenum-containing enzymes such as aldehyde oxidase and xanthine oxidase, although their physiological roles are by no means clear. 

Thus, although histamine may play a physiological role in cardiovascular health, excess histamine, a result of physical or emotional stress or a chronic disease/inflammatory state, appears to elicit atherogenic effects. In fact, inhibition of histamine synthesis in experimental diabetes reduced aortic albumin accumulation in experimental diabetes, lessening the disease complications (Hollis et al, 1983). 

Beta Adrenoceptor Agonists - Beta adrenoceptors have been divided into subclasses based on the relative activities of various sympathomimetic amines on different target tissues. For example, beta-1 receptors are found in the heart and beta-2 receptors are found in bronchlolar and other smooth muscle. The potent beta adrenoceptor stimulant Isoproterenol, a common agent for the treatment of asthma, is nonselectlve and may cause undesirable cardiac stimulation at doses which relax bronchlolar smooth muscle. Besides direct effects on bronchial smooth muscle, these compounds inhibit mediator release from skln or passively sensitized human lung and also inhibit antigen-stimulated histamine synthesis in human leucocytes. ... 

In 1966, the name was proposed (5) for receptors blocked by the at that time known antihistamines. It was also speculated that the other actions of histamine were likely to be mediated by other histamine receptors. The existence of the H2 receptor was accepted in 1972 (6) and the receptor was recognized in rat brain in 1983 (7). receptors in the brain appear to be involved in the feedback control of both histamine synthesis and release, whereas release of various other neurotransmitters, eg, serotinin (5-HT), dopamine, noradrenaline, and acetylcholine, is also modulated (8) (see Neuroregulators). 

Synthesis. Histamine [51-45-6] 2-(4-imidazolyl)ethylarnine (1) is formed by decarboxylation of histidine by the enzyme L-histidine decarboxylase (Fig. 1). Most histamine is stored preformed in cytoplasmic granules of mast cells and basophils. In humans mast cells are found in the loose connective tissue of all organs, especially around blood and lymphatic vessels and nerves. These cells are most abundant in the organs expressing allergic diseases the skin, respiratory tract, and gastrointestinal tract. 

Astemi2ole (10) has further been modified into a series of 4-phenylcyclohexylamine compounds, resulting in the synthesis of cabastine, for example. Cabastine is a highly active compound and its geometric isomers are also active, demonstrating the stereoselectivity of histamine receptors toward chiral ligands. The > S, 4 R-levo antipode of cabastine was the most active, and therefore this isomer, levocabastine (13), has been chosen for further development. Because of high potency, levocabastine has been developed for topical appHcation such as eye drops and nasal spray. 

Although mast cells and basophils probably account for >90% of stored histamine in the body, histamine is also present in platelets, enterochromaffin-like cells, endothelial cells, and neurons. Histamine can act as a neurotransmitter in the brain. Histaminergic nerves have their cell bodies within a very small area of the brain (the magnocellular nuclei of the posterior hypothalamus) but have axons in most areas of the forebrain. There is also evidence for axons projecting into the spinal (Fig. 1) cord. Finally, there is evidence that histamine synthesis can be induced in tissues undergoing rapid tissue growth and repair. In certain neonatal tissues (e.g. liver), the rate of synthesis of this unstored diffusable histamine (termed nascent histamine) is profound and may point to a role for histamine is cell proliferation. 

The human histamine Hi-receptor is a 487 amino acid protein that is widely distributed within the body. Histamine potently stimulates smooth muscle contraction via Hi-receptors in blood vessels, airways and in the gastrointestinal tract. In vascular endothelial cells, Hi-receptor activation increases vascular permeability and the synthesis and release of prostacyclin, plateletactivating factor, Von Willebrand factor and nitric oxide thus causing inflammation and the characteristic wheal response observed in the skin. Circulating histamine in the bloodstream (from, e.g. exposure to antigens or allergens) can, via the Hi-receptor, release sufficient nitric oxide from endothelial cells to cause a profound vasodilatation and drop in blood pressure (septic and anaphylactic shock). Activation of... 

The development and use in peptide synthesis of the 1-adamantyloxymethyl protecting group for N -histidine 28 was reported <9 CS(P1)2139>. A procedure for the regiospecific alkylation of histidine and histamine at N-l(t) via the corresponding tetrahydro oximidazo[l,5-c]pyrimidines 29 was also developed <96T5363>. 

Suggest a synthesis for (19), needed in the search for new anti-histamines. 

Histamine is synthesised by decarboxylation of histidine, its amino-acid precursor, by the specific enzyme histidine decarboxylase, which like glutaminic acid decarboxylase requires pyridoxal phosphate as co-factor. Histidine is a poor substrate for the L-amino-acid decarboxylase responsible for DA and NA synthesis. The synthesis of histamine in the brain can be increased by the administration of histidine, so its decarboxylase is presumably not saturated normally, but it can be inhibited by a fluoromethylhistidine. No high-affinity neuronal uptake has been demonstrated for histamine although after initial metabolism by histamine A-methyl transferase to 3-methylhistamine, it is deaminated by intraneuronal MAOb to 3-methylimidazole acetic acid (Fig. 13.4). A Ca +-dependent KCl-induced release of histamine has been demonstrated by microdialysis in the rat hypothalamus (Russell et al. 1990) but its overflow in some areas, such as the striatum, is neither increased by KCl nor reduced by tetradotoxin and probably comes from mast cells. 

Figure 6.1 Histamine synthesis and metabolism in neurons. L-histidine is transported into neurons by the L-amino acid transporter. Once inside the neuron, L-histidine is converted into histamine by the specific enzyme histidine decarboxylase. Subsequently, histamine is taken up into vesicles by the vesicular monoamine transporter and stored there until released. In the absence of a high-affinity uptake mechanism in the brain, released histamine is rapidly degraded by histamine methyltransferase, which is located postsynaptically and in glia, to telemethylhistamine, a metabolite that does not show any histamine-like activity.

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