Characterization and development of cimetidine as a histamine H2-receptor antagonist

Brimblecombe, R. W.; Duncan, W. A. M.; Durant, G. J.; Emmett, J. C.; Ganellin, C. Robin; Leslie, G.B.; Parsons, M E

doi:10.1016/0016-5085(78)90758-8

Cited by 182 publications

(40 citation statements)

References 20 publications

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“…Inhibition of PI3K has no effect on resting glands or glands maximally stimulated with histamine plus IBMX. It is now commonly accepted that histamine is the main stimulant of the gastric parietal cell (8,10). Stimulation begins with the agonist, histamine, binding to the G coupled-protein H 2 receptor, dissociating the G␣␤␥ complex, and causing the G␣ subunit to activate adenylyl cyclase, thus increasing the intracellular cAMP level, the activation of PKA, and the phosphorylation of numerous proteins responsible for the trafficking and recruitment of H-K-ATPase-rich tubulovesicles to the apical membrane (14,17).…”

Section: Enhanced Stimulation By Pi3k Inhibition Requires H 2 Receptomentioning

confidence: 99%

Modulatory role of phosphoinositide 3-kinase in gastric acid secretion

Mettler¹,

Ghayouri²,

Christensen³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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The gastric parietal cell is responsible for the secretion of HCl into the lumen of the stomach mainly due to stimulation by histamine via the cAMP pathway. However, the participation of several other receptors and pathways have been discovered to influence both stimulation and inhibition of acid secretion (e.g., cholinergic). Here we examine the role of phosphoinositide 3-kinase (PI3K) in the modulation of acid secretion. Treatment of isolated gastric glands and parietal cells with the PI3K inhibitor, LY294002 (LY), potentiated acid secretion in response to histamine to nearly the maximal secretion obtained with histamine plus phosphodiesterase inhibitors. As cAMP levels were elevated in response to histamine plus LY, but other means of elevating cAMP (e.g., forskolin, dbcAMP) were not influenced by LY, we posited that the effect might require activation of G-protein-coupled histamine H(2) receptors, possibly through the protein kinase B pathway (also known as Akt). Study of downstream effectors of PI3K showed that histaminergic stimulation increased Akt phosphorylation, which in turn was blocked by inhibition of PI3K. Expression studies showed that high expression of active Akt decreased acid secretion, whereas dominant-negative Akt increased acid secretion. Taken together, these data suggest stimulation with histamine increases the activity of PI3K leading to increased activity of Akt and decreased levels of cAMP in the parietal cell.

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Section: Enhanced Stimulation By Pi3k Inhibition Requires H 2 Receptomentioning

confidence: 99%

Modulatory role of phosphoinositide 3-kinase in gastric acid secretion

Mettler¹,

Ghayouri²,

Christensen³

et al. 2007

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…By using impromidine, Baumann and co-workers demonstrated that H 2 R stimulation may be an effective treatment in patients suffering from severe catecholamine-insensitive congestive heart failure [67]. Arpromidine (9) and related N-…”

Section: Guanidines As H 2 Receptor Agonistsmentioning

confidence: 99%

“…(5). Putative binding of (a) impromidine (7) and (b) arpromidine (9), respectively, to gpH 2 R. The TM regions are schematically represented as ribbons in spectral colours: TM1 -red, TM2 -orange, TM3 -yellow, TM4 -green blue, TM5 -cyan, TM6 -blue, TM7 -violet. Amino acids of the binding site are denoted in the tone of their TM.…”

Section: Bzmentioning

confidence: 99%

“…The discovery and pharmacological characterisation of the H 2 R by Black and collaborators in 1972 [7] is closely associated with one of the greatest success stories in drug research at all, i.e. the search for H 2 R antagonists as drugs for the treatment of gastric and duodenal ulcer resulting in the development of cimetidine and its introduction into clinic about 30 years ago [8,9]. The application of H 2 R antagonists has provided evidence for an important physiological role of histamine (1, Fig.…”

Section: Introductionmentioning

confidence: 99%

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Structure-Activity Relationships of Histamine H2 Receptor Ligands+

Dove¹,

Elz²,

Seifert³

et al. 2004

MRMC

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Recent research on histamine H2 receptor agonists was focused on quantitative structure-activity relationships and receptor models explaining the activity of imidazolylpropylguanidines. Their selectivity for guinea pig vs. human isoforms was investigated using H2 receptor-Gsalpha fusion proteins and attributed to amino acid differences in transmembrane domains 1 and 7. New antagonists result from approaches to improve pharmacokinetic properties and to design hybrid drugs which additionally have gastroprotective or anti H. pylori activity.

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“…Cimetidine is a histamine H-2 receptor antagonist [Brimblecombe et al, 1978] used worldwide for treating disorders of the esophagus, stomach, and duodenum. Nitrosation of cimetidine produces nitrosocimetidine (NC), a compound that resembles N-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG), a potent genotoxic carcinogen.…”

Section: Cimetidine (Tagamet) and Nitrosocimetidinementioning

confidence: 99%