The approach of treating ulcers was mainly based on the administration of antacids. However, even if the antacids were administered frequently, the production of hydrochloric acid by the parietal cells never ceased. It became wiser to develop agents which could completely block acid production. In later years, it was then discovered that a microbiological agent, Helicobacter pylori was responsible for the delay in healing among patients suffering from asthma.
In total, the interventions in the management and treatment of peptic ulcers have been grouped into three broad categories: proton pump inhibitors (antagonists), antacids and antibiotics to treat the microbe. However, the understanding of the mechanism through which proton pump inhibitors work will result to other new developments which will help in the management of ulcers, a condition that greatly affects the quality of living among patients. Introduction 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 .
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 . 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 . Molecular interaction of Histamine and Histamine analogs with H2 Receptors
Histamine binds to the pockets of the alpha helixes of the transmembrane histamine H2 receptor. Within the phopholipid bilayer of the plasma membrane, there is a specific pocket for small lipophillic biogenic amines. Agonists (histamine) and antagonists (cimetidine) bind to the residues of the receptor within the pocket by means of nonionic and ionic molecular interaction as shown in Fig 1. 1 Fig 1. 1 Agonists and Antagonist Binding to H2 Receptor Fig 1. 1 Model of agonists (histamine) and antagonist (cimetidine) binding to H2 receptor 
Histamine Receptor Subtypes The subtypes of histamine receptors have been established and the major subtypes include H1, H2 and H3 receptors . H2 is the most important in the secretion of gastric acid from the parietal cells of the stomach and the inhibition of H2 receptors potentially reduce the production of the acid among patients suffering from peptic ulcers. These compounds that can successfully block the H2 receptors are known as the H2 receptor antagonists such as cimetidine, ranitidine, nizatidine and famotidine .
Mechanism of H2 Receptor Antagonist H2 antagonists such as cimetidine competitively inhibit histamine H2 receptors with the principal aim of blocking the secretion of gastric acid regardless whether it is of nocturnal, diurnal type or even the type stimulated by foods. The structure of all H2 antagonists has a basic common characteristic and this gives them a competitive property to compete with the molecule, histamine for the active sites of H2 receptors.
The principle of structure-activity relationship (SAR) has been utilized in the making of drug molecules able to block the action of compounds such as histamine which increase the production of the acid by parietal cells . H2 receptor antagonists have also been used in the treatment of dyspepsia. However, latest developments have seen the H2 receptor antagonists being replaced by even more effective proton pump inhibitors Histamine (H2) Receptor Histamine H2 receptors belong to members of a large family of G-protein coupled receptors coded by a number of different genes.
The expression and functionality of the members of G-protein coupled receptors family are highly regulated upon the interaction of agonists or antagonists. Scientists have already established that H2 receptors are rapidly desensitized, down regulated and internalized with the exposure of histamine or other H2 agonists. While modulation of the function of this critical H2 receptor can lead to several insights, research on this area is still limited.
In an experiment conducted on parietal cells in vitro, extended blockade of H2 receptors results into increased sensitivity of parietal cells to H2 agonists . Other observations that were made include the elevated intragastric hyperacidity following an abrupt agonist withdrawal and tolerance development. The molecular studies of the mechanism involving H2 receptors have been made possible with the advent of recombinant DNA technology which allows for cloning of individual gene and having a close study of the expression and functions of genes .
In general, H2 receptors show a spontaneous activity independent on histamine. Further studies on other G protein coupled receptors show that the elevated basal receptor activity independent of the agonists can be suppressed by specific antagonists known as inverse agonists. Although overexposure of G protein coupled receptors to agonists leads to reduced gene expression of the receptors, there can be an upregulation of the receptors especially for inverse agonists. Ranitidine and Cimetidine act inversely as agonists while binding to the H2 receptor .
This inverse agonism displayed by ranitidine and cimetidine suggest the mechanism for the commonly made observation of the H2 antagonist-induced H2 receptor upregulation in experimental Chinese hamster ovary (CHO) cells . The H2 receptors belong to the G protein-coupled receptor (GPCR) family which is also comprised of up to 800 members of membrane protein receptors. The membrane receptors have seven (7) segments spanning the cell membrane and have two termini: the amino and carboxyl termini which are essential for signal transduction.
In general, the G protein coupled receptors form the largest family of signaling receptors in the entire human genome . Fig 1. 2 The structure of Histamine H2 Receptor Fig 1. 1 The structure of Histamine H2 Receptor: the seven transmembrane segments can be seen to span the cell membrane (adapted from Valle and Grantz ) Cimetidine: definition and structure Cimetidine is a histamine congener which inhibits the binding of histamine competitively to H2 receptors.
After its binding to the H2 receptor, cimetidine causes a range of pharmacological responses through the inhibition of secretion of gastric acid by parietal cells as well as gastrin and pepsin output. Cimetidine also acts to block cytochrome P-450 activity and it may therefore be used in future as a neoadjuvant therapy. Cimetidine reduces the nocturnal and basal secretion of gastric acid and also reduces acidity, gastric volume as well as the amount of released acid upon particular stimuli such as caffeine, food, betazole, insulin and pentagastrin.
The structure of cimetidine (Fig 1. 3) permits it to competitively bind to the H2 receptors, the target for histamine. Cimetidine is used in the management of duodenal and gastric ulcers, pathological hepersecretory and gastroesophageol reflux conditions. The inhibition of cytochrome P-450 has raised increased attention as it interferes with the metabolism of drugs and other xenobiotics. Fig 1. 3 Structure of Cimetidine Fig 1. 3 The structure of cimetidine gives it the competitive ability to bind to H2 receptors just like histamine  Conclusion
The studies of receptor-ligand interactions have been critical in areas of pharmaceutical research. The analysis of physical properties of compounds has moved a whole new level where computer-assisted designs can be made and extrapolated to the real-life situation. Molecules can be interacted with a number of receptors using computer software to come up with conclusive report. This approach of drug discovery is fast and does not face ethical issues surrounding the animal and human experiments. Bibliography: Smith, MJ. , Leurs, RL. , Alewinjnse, AE.
, Blauw, J. , Van Nieuw Amerongen, GP. , De Vrede, YV. , Roovers, E. , & Timmerman, H. Inverse agonism of histamine H2 antagonists accounts for upregulation of spontaneously active histamine H2 receptors, Proc. Natl. Acad. Sci. USA, 1996; 93: 6802-6807 Valle, JD & Grantz, I. Novel insights into histamine H2 receptor biology. Am J Physiol Gastrointest Liver Physiol 1997; 273(5): G987-G996 Vogel, HG. Drug Discovery and Evaluation: Pharmacological Assays. New York: Springer, 2008 Kobilka, BK. G protein coupled receptor structure and activation.
Biochemical and Biophysics Academy, 2007; 1768 (4): 794-807 Harmar, AJ. Family –B G-protein-couples receptors. Genome Biology, 2001; 2(12): 312- 316 Haines, C. A common heartburn remedy complements conventional cancer therapy. 2007, Accessed 21st August, 2010, from, http://www. lef. org/magazine/mag2007/may2007_report_cimetidine_01. htm PharmGKB. Cimetidine, 2010, Accessed, 21st August 2010, from, http://www. pharmgkb. org/do/serve? objId=PA449001#tabview=tab0 Rossing, MA. , Delia S, Cushing-Haugen , KL & Voigt, LF. Cimetidine use and risk of prostate and breast cancer. Cancer Epide