Target Information

Target General Infomation
Target ID
T30985
Former ID
TTDS00087
Target Name
Histamine H2 receptor
Gene Name
HRH2
Synonyms
Gastric receptor I; H2R; Histamine receptor 2; HRH2
Target Type
Successful
Disease Acid-reflux disorders [ICD9: 530.81; ICD10: K21]
Duodenal ulcers [ICD10: K25-K27]
Gastroesophageal reflux disease [ICD9: 140-229, 530; ICD10: K21]
Gastric ulcer [ICD9: 531; ICD10: K25]
Gastric secretory disorders [ICD9: 536.8; ICD10: K30]
Peptic ulcer [ICD9: 531-534; ICD10: K25-K27]
Pain [ICD9: 338, 356.0, 356.8,780; ICD10: G64, G90.0, R52, G89]
Stomach ulcer [ICD10: K25-K27]
Ulcerative colitis [ICD9: 556; ICD10: K51]
Function
The H2 subclass of histamine receptors mediates gastric acid secretion. Also appears to regulate gastrointestinal motility and intestinal secretion. Possible role in regulating cell growth and differentiation. The activity of this receptor is mediated by G proteins which activate adenylyl cyclase and, through a separate G protein-dependent mechanism, the phosphoinositide/protein kinase (PKC) signaling pathway (By similarity).
BioChemical Class
GPCR rhodopsin
Target Validation
T30985
UniProt ID
P25021
Sequence
MAPNGTASSFCLDSTACKITITVVLAVLILITVAGNVVVCLAVGLNRRLRNLTNCFIVSL
AITDLLLGLLVLPFSAIYQLSCKWSFGKVFCNIYTSLDVMLCTASILNLFMISLDRYCAV
MDPLRYPVLVTPVRVAISLVLIWVISITLSFLSIHLGWNSRNETSKGNHTTSKCKVQVNE
VYGLVDGLVTFYLPLLIMCITYYRIFKVARDQAKRINHISSWKAATIREHKATVTLAAVM
GAFIICWFPYFTAFVYRGLRGDDAINEVLEAIVLWLGYANSALNPILYAALNRDFRTGYQ
QLFCCRLANRNSHKTSLRSNASQLSRTQSREPRQQEEKPLKLQVWSGTEVTAPQGATDR
Drugs and Mode of Action
Drug(s) Betazole Drug Info Approved Gastric secretory disorders [1], [2]
Cimetidine Drug Info Approved Acid-reflux disorders [3], [4]
Famotidine Drug Info Approved Peptic ulcer [5], [6]
Nizatidine Drug Info Approved Acid-reflux disorders [7], [8]
Ranitidine Drug Info Approved Peptic ulcer [5], [9]
Ebrotidine Drug Info Withdrawn from market Duodenal ulcers [10]
KU-1257 Drug Info Discontinued in Phase 3 Duodenal ulcers [11]
Osutidine Drug Info Discontinued in Phase 3 Duodenal ulcers [12]
Pibutidine Drug Info Discontinued in Phase 3 Ulcerative colitis [13]
IGN-2098 Drug Info Discontinued in Phase 2 Duodenal ulcers [14]
Lavoltidine Drug Info Discontinued in Phase 2 Gastroesophageal reflux disease [15]
CP-66948 Drug Info Discontinued in Phase 1 Gastric ulcer [16]
TRM-115 Drug Info Discontinued in Phase 1 Gastric ulcer [17]
Z-300 Drug Info Discontinued in Phase 1 Gastric ulcer [18]
CP-331 Drug Info Terminated Pain [19]
FRG-8701 Drug Info Terminated Stomach ulcer [20]
Inhibitor (+/-)-nantenine Drug Info [21]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info [22]
VUF-10148 Drug Info [23]
WAY-207024 Drug Info [24]
Agonist amthamine Drug Info [25]
arpromidine Drug Info [26]
burimamide Drug Info [27]
Dimaprit Drug Info [28]
impromidine Drug Info [26]
oxo-arpromidine Drug Info [26]
UR-PG146 Drug Info [26]
Antagonist Betazole Drug Info [29]
Cimetidine Drug Info [30], [31], [32]
CP-66948 Drug Info [33], [28]
Famotidine Drug Info [34], [30], [35], [36], [32]
Gaster Drug Info [37], [38]
IGN-2098 Drug Info [39]
iodoaminopotentidine Drug Info [40]
KU-1257 Drug Info [41]
Lavoltidine Drug Info [42]
Metiamide Drug Info [43]
Nizatidine Drug Info [44]
Osutidine Drug Info [45]
Ranitidine Drug Info [46], [37], [32]
tiotidine Drug Info [40]
TRM-115 Drug Info [47]
Z-300 Drug Info [48], [28]
[125I]iodoaminopotentidine Drug Info [49]
[3H]tiotidine Drug Info [50]
Modulator CP-331 Drug Info [51]
Ebrotidine Drug Info [52]
FRG-8701 Drug Info [20]
Pibutidine Drug Info [53]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Calcium signaling pathway
Neuroactive ligand-receptor interaction
Gastric acid secretion
PANTHER Pathway Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway
Histamine H2 receptor mediated signaling pathway
PathWhiz Pathway Intracellular Signalling Through Histamine H2 Receptor and Histamine
Gastric Acid Production
Reactome Histamine receptors
G alpha (s) signalling events
WikiPathways Monoamine GPCRs
GPCRs, Class A Rhodopsin-like
Secretion of Hydrochloric Acid in Parietal Cells
GPCR ligand binding
GPCR downstream signaling
References
REF 1(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7126).
REF 2Drug information of Betazole, 2008. eduDrugs.
REF 3FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 074151.
REF 4(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1231).
REF 5Clinical review of histamine2 receptor antagonists. Arch Intern Med. 1990 Apr;150(4):745-51.
REF 6(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7074).
REF 7FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075616.
REF 8(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7248).
REF 9(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 1234).
REF 10Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001139)
REF 11Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001852)
REF 12Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002012)
REF 13Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000641)
REF 14Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001447)
REF 15Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000092)
REF 16Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001137)
REF 17Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002138)
REF 18Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001448)
REF 19Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001767)
REF 20Effects of FRG-8701 on gastric acid secretion, gastric mucosal lesions by necrotizing agents and experimental gastric or duodenal ulcer in rats. Jpn J Pharmacol. 1990 Nov;54(3):277-85.
REF 21Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. Epub 2009 Nov 20.Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine.
REF 22J Med Chem. 2010 Sep 9;53(17):6386-97.Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 receptor agonist with unprecedented selectivity and procognitive potential.
REF 23J Med Chem. 2008 Apr 24;51(8):2457-67. Epub 2008 Mar 22.Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo.
REF 24J Med Chem. 2009 Apr 9;52(7):2148-52.Discovery of 6-({4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl}methyl)quinoxaline (WAY-207024): an orally active antagonist of the gonadotropin releasing hormone receptor (GnRH-R).
REF 25N(G)-acylated aminothiazolylpropylguanidines as potent and selective histamine H(2) receptor agonists. ChemMedChem. 2009 Feb;4(2):232-40.
REF 26Probing ligand-specific histamine H1- and H2-receptor conformations with NG-acylated Imidazolylpropylguanidines. J Pharmacol Exp Ther. 2006 Apr;317(1):139-46. Epub 2006 Jan 4.
REF 27Constitutive activity and structural instability of the wild-type human H2 receptor. J Neurochem. 1998 Aug;71(2):799-807.
REF 28Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
REF 29Effect of nizatidine and cimetidine on betazole-stimulated gastric secretion of normal subjects: comparison of effects on acid, water, and pepsin. Am J Gastroenterol. 1988 Jan;83(1):32-6.
REF 30Histamine H1 and H2 receptor antagonists accelerate skin barrier repair and prevent epidermal hyperplasia induced by barrier disruption in a dry environment. J Invest Dermatol. 2001 Feb;116(2):261-5.
REF 31Characterization and modulation of antigen-induced effects in isolated rat heart. J Cardiovasc Pharmacol. 1991 Oct;18(4):556-65.
REF 32Effect of the H2 histamine receptor antagonist on oxygen metabolism in some morphotic blood elements in patients with ulcer disease. Hepatogastroenterology. 1998 Jan-Feb;45(19):276-80.
REF 33CP-66,948: an antisecretory histamine H2-receptor antagonist with mucosal protective properties. Dig Dis Sci. 1991 Dec;36(12):1721-8.
REF 34Blastocyst H(2) receptor is the target for uterine histamine in implantation in the mouse. Development. 2000 Jun;127(12):2643-51.
REF 35Analysis of Vancomycin in the Hindlimb Vascular Bed of the Rat. Am J Ther. 1996 Oct;3(10):681-687.
REF 36Pharmacological control of the human gastric histamine H2 receptor by famotidine: comparison with H1, H2 and H3 receptor agonists and antagonists. Eur J Clin Invest. 1989 Feb;19(1):1-10.
REF 37Knockouts model the 100 best-selling drugs--will they model the next 100? Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
REF 38Afferent signalling from the acid-challenged rat stomach is inhibited and gastric acid elimination is enhanced by lafutidine. BMC Gastroenterol. 2009 Jun 2;9:40.
REF 39Effects of IGN-2098, a new histamine H2-receptor antagonist, on gastric secretion and gastric and duodenal lesions induced in rats. Comparison with roxatidine. Nihon Yakurigaku Zasshi. 1992 Mar;99(3):167-80.
REF 40Heterologous expression of rat epitope-tagged histamine H2 receptors in insect Sf9 cells. Br J Pharmacol. 1997 Nov;122(5):867-74.
REF 41Pharmacological profiles of the new histamine H2-receptor antagonist N-ethyl-N'-[3-[3-(piperidinomethyl)phenoxy] propyl] urea. Arzneimittelforschung. 1993 Feb;43(2):129-33.
REF 42New and Future Drug Development for Gastroesophageal Reflux Disease. J Neurogastroenterol Motil. 2014 January; 20(1): 6-16.
REF 43Metiamide—an orally active histamine H2-receptor antagonist. 1973. Agents Actions. 1994 Dec;43(3-4):91-5; discussion 96.
REF 44Does the use of nizatidine, as a pro-kinetic agent, improve gastric emptying in patients post-oesophagectomy? J Gastrointest Surg. 2009 Mar;13(3):432-7. Epub 2008 Nov 1.
REF 45Effects of osutidine (T-593) and its enantiomers on gastric mucosal hemodynamics and mucosal integrity in anesthetized rats. Arzneimittelforschung. 2001 Jan;51(1):46-50.
REF 46Hemodynamic significance of histamine synthesis and histamine H1- and H2-receptor gene expression during endotoxemia. Naunyn Schmiedebergs Arch Pharmacol. 2002 Dec;366(6):513-21. Epub 2002 Oct 29.
REF 47Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002138)
REF 48Effects of a new histamine H2-receptor antagonist, Z-300, on gastric secretion and gastro-duodenal lesions in rats: comparison with roxatidine. Jpn J Pharmacol. 1992 Jul;59(3):275-89.
REF 49G proteins of the Gq family couple the H2 histamine receptor to phospholipase C. Mol Endocrinol. 1996 Dec;10(12):1697-707.
REF 50Tiotidine, a histamine H2 receptor inverse agonist that binds with high affinity to an inactive G-protein-coupled form of the receptor. Experimental support for the cubic ternary complex model. Mol Pharmacol. 2003 Aug;64(2):512-20.
REF 51Conjugation of chlorin p(6) to histamine enhances its cellular uptake and phototoxicity in oral cancer cells. Cancer Chemother Pharmacol. 2011 Aug;68(2):359-69.
REF 52Histamine H2-receptor antagonist action of ebrotidine. Effects on gastric acid secretion, gastrin levels and NSAID-induced gastrotoxicity in the rat. Arzneimittelforschung. 1997 Apr;47(4A):439-46.
REF 53Comparative pharmacology of epibatidine: a potent agonist for neuronal nicotinic acetylcholine receptors. Mol Pharmacol. 1995 Oct;48(4):774-82.

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