Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTQHJ1K)

• DTT Name: Histamine H2 receptor (H2R)
• Synonyms: Histamine receptor 2; HH2R; Gastric receptor I
• Gene Name: HRH2
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: HRH2_HUMAN
• TTD ID: T30985
• Sequence:
  MAPNGTASSFCLDSTACKITITVVLAVLILITVAGNVVVCLAVGLNRRLRNLTNCFIVSL
  AITDLLLGLLVLPFSAIYQLSCKWSFGKVFCNIYTSLDVMLCTASILNLFMISLDRYCAV
  MDPLRYPVLVTPVRVAISLVLIWVISITLSFLSIHLGWNSRNETSKGNHTTSKCKVQVNE
  VYGLVDGLVTFYLPLLIMCITYYRIFKVARDQAKRINHISSWKAATIREHKATVTLAAVM
  GAFIICWFPYFTAFVYRGLRGDDAINEVLEAIVLWLGYANSALNPILYAALNRDFRTGYQ
  QLFCCRLANRNSHKTSLRSNASQLSRTQSREPRQQEEKPLKLQVWSGTEVTAPQGATDR
• Function: 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. The H2 subclass of histamine receptors mediates gastric acid secretion.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Gastric acid secretion (hsa04971)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Histamine receptors (R-HSA-390650)

Molecular Interaction Atlas (MIA) of This DTT

5 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Betazole	DMUFGAY	Gastric secretory disorder	DD90	Approved	[2]
Cimetidine	DMH61ZB	Acid-reflux disorder	DA22	Approved	[1]
Famotidine	DMRL3AB	Gastric ulcer	DA60	Approved	[1]
Nizatidine	DMGFV3Z	Acid-reflux disorder	DA22	Approved	[3]
Ranitidine	DM0GUSX	Gastric ulcer	DA60	Approved	[4]

11 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Ebrotidine	DMV5KR3	Duodenal ulcer	DA63	Withdrawn from market	[5]
KU-1257	DMZMFX6	Duodenal ulcer	DA63	Discontinued in Phase 3	[6]
Osutidine	DMN7TL8	Duodenal ulcer	DA63	Discontinued in Phase 3	[7]
Pibutidine	DMXSTRM	Ulcerative colitis	DD71	Discontinued in Phase 3	[8]
IGN-2098	DMU4N1O	Duodenal ulcer	DA63	Discontinued in Phase 2	[9]
Lavoltidine	DMTY5VE	Gastroesophageal reflux disease	DA22.Z	Discontinued in Phase 2	[10]
CP-66948	DMTM0UI	Gastric ulcer	DA60	Discontinued in Phase 1	[11]
TRM-115	DMSFV9T	Gastric ulcer	DA60	Discontinued in Phase 1	[12]
Z-300	DMA412G	Gastric ulcer	DA60	Discontinued in Phase 1	[13]
CP-331	DMCIXYR	Pain	MG30-MG3Z	Terminated	[14]
FRG-8701	DMC5O3X	Stomach ulcer	DA60.Z	Terminated	[15]

15 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+/-)-nantenine	DM0L3GE	Discovery agent	N.A.	Investigative	[16]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one	DMM9X0G	Discovery agent	N.A.	Investigative	[17]
amthamine	DMBAX3P	Discovery agent	N.A.	Investigative	[18]
arpromidine	DMB9PDA	Discovery agent	N.A.	Investigative	[19]
burimamide	DMZ2VYG	Discovery agent	N.A.	Investigative	[20]
Dimaprit	DMA4NI2	Discovery agent	N.A.	Investigative	[21]
impromidine	DMTDRPM	Discovery agent	N.A.	Investigative	[19]
iodoaminopotentidine	DM7AHNF	Discovery agent	N.A.	Investigative	[22]
Metiamide	DMO7JGS	Discovery agent	N.A.	Investigative	[23]
oxo-arpromidine	DMV0KTW	Discovery agent	N.A.	Investigative	[19]
tiotidine	DM81KD2	Discovery agent	N.A.	Investigative	[22]
UR-PG146	DMQCL6Y	Discovery agent	N.A.	Investigative	[19]
VUF-10148	DM89PMC	Discovery agent	N.A.	Investigative	[24]
WAY-207024	DMJ14NE	Discovery agent	N.A.	Investigative	[25]
[125I]iodoaminopotentidine	DMHJL58	Discovery agent	N.A.	Investigative	[26]

References

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• [6] Pharmacological profiles of the new histamine H2-receptor antagonist N-ethyl-N'-[3-[3-(piperidinomethyl)phenoxy] propyl] urea. Arzneimittelforschung. 1993 Feb;43(2):129-33.
• [7] Effects of osutidine (T-593) and its enantiomers on gastric mucosal hemodynamics and mucosal integrity in anesthetized rats. Arzneimittelforschung. 2001 Jan;51(1):46-50.
• [8] Comparative pharmacology of epibatidine: a potent agonist for neuronal nicotinic acetylcholine receptors. Mol Pharmacol. 1995 Oct;48(4):774-82.
• [9] Effects 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.
• [10] New and Future Drug Development for Gastroesophageal Reflux Disease. J Neurogastroenterol Motil. 2014 January; 20(1): 6-16.
• [11] CP-66,948: an antisecretory histamine H2-receptor antagonist with mucosal protective properties. Dig Dis Sci. 1991 Dec;36(12):1721-8.
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• [18] N(G)-acylated aminothiazolylpropylguanidines as potent and selective histamine H(2) receptor agonists. ChemMedChem. 2009 Feb;4(2):232-40.
• [19] Probing ligand-specific histamine H1- and H2-receptor conformations with NG-acylated Imidazolylpropylguanidines. J Pharmacol Exp Ther. 2006 Apr;317(1):139-46.
• [20] Constitutive activity and structural instability of the wild-type human H2 receptor. J Neurochem. 1998 Aug;71(2):799-807.
• [21] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015
• [22] Heterologous expression of rat epitope-tagged histamine H2 receptors in insect Sf9 cells. Br J Pharmacol. 1997 Nov;122(5):867-74.
• [23] Metiamide--an orally active histamine H2-receptor antagonist. 1973. Agents Actions. 1994 Dec;43(3-4):91-5; discussion 96.
• [24] Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo. J Med Chem. 2008 Apr 24;51(8):2457-67.
• [25] 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 ... J Med Chem. 2009 Apr 9;52(7):2148-52.
• [26] G proteins of the Gq family couple the H2 histamine receptor to phospholipase C. Mol Endocrinol. 1996 Dec;10(12):1697-707.