Cimetidine is the most prototypical drug ever to be tested and shown to have exciting antagonistic properties with histamine H2-receptor. After GlaxoSmithKline’s development in about mid 1960s, a number of histamine H2 receptor antagonists have been developed. H2 receptor antagonists belong to classes of drugs which block histamine action on the parietal cells mainly in the stomach. They do this by inhibiting acid production by parietal cells which is the leading worst conditions experienced by patients suffering from peptic ulcers.
The H2-receptor antagonists’ discovery came many several after the discovery of H1-receptor antagonists [1]. All in all, after the introduction of cimetidine in the market, other drugs were in the pipeline and this saw the introduction of ranitidine, nizatidine and famotidine thereafter. Histamine Histamine, chemically [2-(4-Imidazolyl) ethylamine] is a biogenic amine which has been shown to exert a number of biological responses by binding to the receptors H1, H2 and H3 [2].
One of the most studied responses due to histamine is the potentiation of the production of gastric acid from the parietal cells. Recent studies have been reported that histamine takes part in the regulation of intestinal secretion and gastrointestinal motility. The potential function of H2 receptor in the cell differentiation and growth has also been investigated. The binding of histamine to H2 receptors causes positive inotropic and chronotropic effect to the heart.
The blood vessels become dilated and there is relaxation of extravascular bronchial and smooth muscles. Gastric secretion of HCL increases and this is important feature in peptic ulcers. Immunoregulatory effects such as allergy are not unusual with histaime-H2 receptor binding and cellular hyperpolarization of the central nervous system can also result. Efforts of molecular cloning have revealed that the biogenic amine, histamine has similar configuration to that of the heptahelical G protein-couples receptor.
Further site-directed mutagenesis has also revealed the presence of integral amino acids in position 3 and 4 of the transmembrane domains which are critical for the reorganization of ligands. The mechanism behind the internalization and desensitization has also been deciphered and has been linked to the structure of H2 receptors. While earlier studies showed that H2 receptor exclusively couple to the pathway of adenylate cyclase, it has been shown recently using cloned receptors that H2 receptors are able to activate phosphoinositide signaling cascades via an independent mechanism controlled by G protein [3].