Histamine and its receptor
PHAR3014 Medicinal Chemistry & Drug Design
Properties
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IUPAC name: 2-(1H-imidazol-4-yl)ethanamine
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Melting point: 84°C
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Readily soluble in water, ethanol but insoluble in ether
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In aqueous solution, histamine exists in two tautomeric forms which are Nπ-H-histamine and Nτ-H-histamine
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Nitrogen situated furthest away from the side chain is named 'tele' nitrogen (Nτ)
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Tele-tautomer is preferred in aqueous solution
Storage & release
Histamine is formed through the process decarboxylation of amino acid L-histidine with the help of enzyme histidine decarboxylase (HDC). Back in the 1950s, histamine storage in body was discovered. Histamine was found to be stored in mast cells and basophils. Reduced amount of histamine is linearly correlated to disrupted mast cells. Additional sources of histamine are blood basophil, blood platelets and the enterochromaffin-like cell (ECL) in the stomach (Parsons and Ganellin, 2006). In general, histamine can be found abundantly in the skin, connective tissue and the gastrointestinal tract. Histamine is released during anaphylactic shock following initiation of the degranulation process.
During an inflammation, histamine is released abundantly. However, our body nature will counteract it metabolised the histamine to maintain homeostasis. Two enzymes play a major role in catabolising histamine are histamine N-methyltransferase (HMT) and diamine oxidase forming N-methylhistamine and imidazole acetic acid. The half-life of pharmacologically active doses of histamine is less than 10s in rat and 20-30s in dog.
Metabolism
Histamine-brain relationship
Based on research and study over the years, histamine does not pass through the blood-brain barrier and it was believed that the function of histamine receptors in the brain was to respond to the action of endogenously released mediator (Brzezińska and Kośka, 2006). However, histaminergic neurons were found abundantly in the brain.
It is possible to detect mast cells in the brain and peripheral nerve although the histamine content in mast cells is quite substantial using a cytochemical method. It has been estimated that histamine content of brain regions and nerve trunks that show approximately 50 ng histamine per gram.
Histaminergic neurons are localized in the tuberomammillary nucleus of the hypothalamus and are involved in the regulation of sleep and wakefulness cycle, feeding and memory processes. On the other hand, most of the H1-receptor antagonist in the brain are lipophilic compounds and are able to penetrate the blood-brain barrier. This explains the sedative effect patient encounter while taking an antihistamine.
Figure 4 Tautomers of histamine
Figure 5 The formation of histamine catalyzed by histidine decarboxylase.
Figure 6 Metabolism of histamine through histamine N-methyltransferase.
Figure 7 Metabolism of histamine through diamine oxidase.