H2 Receptor Antagonists

Histamine (Figure 1) was discovered by Dale, but a pupil of Pavlov, Piopielski, first described the stimulation of gastric acid secretion. There was much argument whether histamine or gastrin was the major direct stimulant of the parietal cell. In the 1950s, a series of histamine antagonists was synthesized, where the imidazole ring of histamine was modified to other aromatic structures by Bovet and co-workers.20 These antagonists blocked the peripheral actions of histamine, such as vasodilation and mucus secretion, but had relatively little effect on acid secretion. It was therefore suggested that the histamine receptor in the stomach was a different subtype, a putative H2 receptor, as contrasted to the H1 receptor that was blocked by the compounds synthesized by Bovet. In 1963, Black began work on the synthesis and evaluation of compounds able to selectively block the H2 receptor. By modifying the side chain rather than the imidazole ring of histamine. The first H2 receptor antagonist, burimamide, was synthesized in 1970, rapidly followed by metiamide and cimetidine (Figure 1).1'14 The last was the first H2 receptor antagonist in 1977, marketed as Tagamet. Ranitidine, famotidine, and nizatidine were second-generation H2 receptor antagonists where the imidazole ring was no longer retained (Figure 1). These all contained a protonatable nitrogen atom at the end of the side chain, and presumably bound to the receptor as cations.

The H2 receptor antagonists effectively abolished gastrin-stimulated acid secretion, but were less effective against cholinergically stimulated acid secretion.14 This resolved the issue as to whether histamine acting at H2 receptors or gastrin was the primary stimulant of acid secretion. It is now accepted that the action of gastrin on acid secretion is due to stimulation of histamine release from the ECL cell, and is not due to a direct action of this hormone on the parietal cell.21 The efficacy of H2 receptor antagonists relies on their plasma half-life, as these are reversible inhibitors. Further, they are all inverse agonists, able to inhibit the receptor even in the absence of histamine. There were attempts to develop noncompetitive H2 receptor antagonists (e.g., loxitidine),22 but unexpected toxicity terminated their

Blood Pressure Health

Blood Pressure Health

Your heart pumps blood throughout your body using a network of tubing called arteries and capillaries which return the blood back to your heart via your veins. Blood pressure is the force of the blood pushing against the walls of your arteries as your heart beats.Learn more...

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