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H2 receptor antagonists are a class of drugs that block the action of histamine on parietal cells (specifically the histamine H2 receptors) in the stomach. This decreases the production of acid. H2 antagonists can be used in the treatment of dyspepsia, but have been surpassed by the more effective〔Eriksson S, Långström G, Rikner L, Carlsson R, Naesdal J. Omeprazole and H2-receptor antagonists in the acute treatment of duodenal ulcer, gastric ulcer and reflux oesophagitis: a meta-analysis (correction appears in Eur J Gastroenterol Hepatol. 1996;8:192 ). Eur J Gastroenterol Hepatol. 1995;7:467-475〕 proton pump inhibitors. The prototypical H2 antagonist, called cimetidine, was developed by Sir James Black〔(【引用サイトリンク】url=http://www.nobelprize.org/nobel_prizes/medicine/laureates/1988/black-bio.html )〕 at Smith, Kline & French (now GlaxoSmithKline) in the mid-to-late 1960s. It was first marketed in 1976 and sold under the trade name Tagamet, which would become the first blockbuster drug. The use of quantitative structure-activity relationships (QSAR) led to the development of other agents—starting with ranitidine, first sold as Zantac—which has fewer adverse effects and drug interactions and is more potent. == History and development == Cimetidine was the prototypical histamine H2-receptor antagonist from which later drugs were developed.. Cimetidine was the culmination of a project at Smith, Kline & French (SK&F; now GlaxoSmithKline) by James W. Black, C. Robin Ganellin, and others to develop a histamine receptor antagonist that would suppress stomach acid secretion. In 1964 it was known that histamine stimulated the secretion of stomach acid, and also that traditional antihistamines had no effect on acid production. From these facts the SK&F scientists postulated the existence of two different types of histamine receptors. They designated the one acted upon by the traditional antihistamines as H1, and the one acted upon by histamine to stimulate the secretion of stomach acid as H2. The SK&F team used a classical design process starting from the structure of histamine. Hundreds of modified compounds were synthesised in an effort to develop a model of the then-unknown H2 receptor. The first breakthrough was ''Nα''-guanylhistamine, a partial H2-receptor antagonist. From this lead, the receptor model was further refined, which eventually led to the development of burimamide, a specific competitive antagonist at the H2 receptor. The burimamide is 100-times more potent than ''Nα''-guanylhistamine, proving it's efficacy on the H2 receptor. The potent of the Burimamide was still insufficient for oral administration. And efforts on further improvement of the structure, based on the structure modification in the stomach due to the acid dissociation constant of the compound, led to the development of metiamide. Metiamide was an effective agent; however, it was associated with unacceptable nephrotoxicity and agranulocytosis. It was proposed that the toxicity arose from the thiourea group, and similar guanidine analogues were investigated until the discovery of cimetidine, which would become the first clinically successful H2 antagonist. Ranitidine (common brand name Zantac) was developed by Glaxo (also now GlaxoSmithKline), in an effort to match the success of Smith, Kline & French with cimetidine. Ranitidine was also the result of a rational drug design process utilising the by-then-fairly-refined model of the histamine H2 receptor and quantitative structure-activity relationships (QSAR). Glaxo refined the model further by replacing the imidazole-ring of cimetidine with a furan-ring with a nitrogen-containing substituent, and in doing so developed ranitidine. Ranitidine was found to have a far-improved tolerability profile (i.e. fewer adverse drug reactions), longer-lasting action, and ten times the activity of cimetidine. Ranitidine was introduced in 1981 and was the world's biggest-selling prescription drug by 1988. The H2-receptor antagonists have since largely been superseded by the even more effective proton pump inhibitors, with omeprazole becoming the biggest-selling drug for many years. 抄文引用元・出典: フリー百科事典『 ウィキペディア（Wikipedia）』 ■ウィキペディアで「H2 antagonist」の詳細全文を読む スポンサード リンク
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