Target Information
| Target General Information | Top | |||||
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| Target ID |
T30985
(Former ID: TTDS00087)
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| Target Name |
Histamine H2 receptor (H2R)
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| Synonyms |
Histamine receptor 2; HH2R; Gastric receptor I
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| Gene Name |
HRH2
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 3 Target-related Diseases | + | ||||
| 1 | Gastro-oesophageal reflux disease [ICD-11: DA22] | |||||
| 2 | Oesophageal/gastroduodenal disorder [ICD-11: DD90] | |||||
| 3 | Peptic ulcer [ICD-11: DA61] | |||||
| 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.
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| BioChemical Class |
GPCR rhodopsin
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| UniProt ID | ||||||
| Sequence |
MAPNGTASSFCLDSTACKITITVVLAVLILITVAGNVVVCLAVGLNRRLRNLTNCFIVSL
AITDLLLGLLVLPFSAIYQLSCKWSFGKVFCNIYTSLDVMLCTASILNLFMISLDRYCAV MDPLRYPVLVTPVRVAISLVLIWVISITLSFLSIHLGWNSRNETSKGNHTTSKCKVQVNE VYGLVDGLVTFYLPLLIMCITYYRIFKVARDQAKRINHISSWKAATIREHKATVTLAAVM GAFIICWFPYFTAFVYRGLRGDDAINEVLEAIVLWLGYANSALNPILYAALNRDFRTGYQ QLFCCRLANRNSHKTSLRSNASQLSRTQSREPRQQEEKPLKLQVWSGTEVTAPQGATDR Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T56O5B | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 5 Approved Drugs | + | ||||
| 1 | Betazole | Drug Info | Approved | Gastric secretory disorder | [2], [3] | |
| 2 | Cimetidine | Drug Info | Approved | Acid-reflux disorder | [4], [5] | |
| 3 | Famotidine | Drug Info | Approved | Peptic ulcer | [6], [7] | |
| 4 | Nizatidine | Drug Info | Approved | Acid-reflux disorder | [8], [9] | |
| 5 | Ranitidine | Drug Info | Approved | Peptic ulcer | [7], [10] | |
| Discontinued Drug(s) | [+] 11 Discontinued Drugs | + | ||||
| 1 | Ebrotidine | Drug Info | Withdrawn from market | Duodenal ulcer | [11] | |
| 2 | KU-1257 | Drug Info | Discontinued in Phase 3 | Duodenal ulcer | [12] | |
| 3 | Osutidine | Drug Info | Discontinued in Phase 3 | Duodenal ulcer | [13] | |
| 4 | Pibutidine | Drug Info | Discontinued in Phase 3 | Ulcerative colitis | [14] | |
| 5 | IGN-2098 | Drug Info | Discontinued in Phase 2 | Duodenal ulcer | [15] | |
| 6 | Lavoltidine | Drug Info | Discontinued in Phase 2 | Gastroesophageal reflux disease | [16] | |
| 7 | CP-66948 | Drug Info | Discontinued in Phase 1 | Gastric ulcer | [17] | |
| 8 | TRM-115 | Drug Info | Discontinued in Phase 1 | Gastric ulcer | [18] | |
| 9 | Z-300 | Drug Info | Discontinued in Phase 1 | Gastric ulcer | [19] | |
| 10 | CP-331 | Drug Info | Terminated | Pain | [20] | |
| 11 | FRG-8701 | Drug Info | Terminated | Stomach ulcer | [21] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Antagonist | [+] 14 Antagonist drugs | + | ||||
| 1 | Betazole | Drug Info | [22] | |||
| 2 | Cimetidine | Drug Info | [1], [23], [24] | |||
| 3 | Famotidine | Drug Info | [1], [24], [25], [26], [27], [28], [29] | |||
| 4 | Nizatidine | Drug Info | [30] | |||
| 5 | Ranitidine | Drug Info | [29], [31], [24] | |||
| 6 | KU-1257 | Drug Info | [33] | |||
| 7 | Osutidine | Drug Info | [34] | |||
| 8 | IGN-2098 | Drug Info | [36] | |||
| 9 | Lavoltidine | Drug Info | [37] | |||
| 10 | CP-66948 | Drug Info | [38], [39] | |||
| 11 | TRM-115 | Drug Info | [40] | |||
| 12 | Z-300 | Drug Info | [41], [39] | |||
| 13 | tiotidine | Drug Info | [48], [49] | |||
| 14 | [125I]iodoaminopotentidine | Drug Info | [52] | |||
| Modulator | [+] 4 Modulator drugs | + | ||||
| 1 | Ebrotidine | Drug Info | [32] | |||
| 2 | Pibutidine | Drug Info | [35] | |||
| 3 | CP-331 | Drug Info | [42] | |||
| 4 | FRG-8701 | Drug Info | [21] | |||
| Inhibitor | [+] 4 Inhibitor drugs | + | ||||
| 1 | (+/-)-nantenine | Drug Info | [43] | |||
| 2 | 4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one | Drug Info | [44] | |||
| 3 | VUF-10148 | Drug Info | [50] | |||
| 4 | WAY-207024 | Drug Info | [51] | |||
| Agonist | [+] 7 Agonist drugs | + | ||||
| 1 | amthamine | Drug Info | [45] | |||
| 2 | arpromidine | Drug Info | [46] | |||
| 3 | burimamide | Drug Info | [47] | |||
| 4 | Dimaprit | Drug Info | [39] | |||
| 5 | impromidine | Drug Info | [46] | |||
| 6 | oxo-arpromidine | Drug Info | [46] | |||
| 7 | UR-PG146 | Drug Info | [46] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Famotidine | Ligand Info | |||||
| Structure Description | CryoEM Structure of Inactive H2R Bound to Famotidine, Nb6M, and NabFab | PDB:7UL3 | ||||
| Method | Electron microscopy | Resolution | 3.00 Å | Mutation | No | [53] |
| PDB Sequence |
ACKITITVVL
25 AVLILITVAG35 NVVVCLAVGL45 NRRLRNLTNC55 FIVSLAITDL65 LLGLLVLPFS 75 AIYQLSCKWS85 FGKVFCNIYT95 SLDVMLCTAS105 ILNLFMISLD115 RYCAVMDPLR 125 YPVLVTPVRV135 AISLVLIWVI145 SITLSFLSIH155 LGWCKVQVNE180 VYGLVDGLVT 190 FYLPLLIMCV200 CYTLMILRLK210 SVRLLSSREK225 DRNLRRITRL235 VLVVVAVFVI 245 CWFPYFTAFV255 YRGLRGDDAI265 NEVLEAIVLW275 LGYANSALNP285 ILYAALNRDF 295 RTGYQQLF
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Pathway Affiliation
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Calcium signaling pathway | hsa04020 | Affiliated Target |
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| Class: Environmental Information Processing => Signal transduction | Pathway Hierarchy | ||
| Neuroactive ligand-receptor interaction | hsa04080 | Affiliated Target |
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| Class: Environmental Information Processing => Signaling molecules and interaction | Pathway Hierarchy | ||
| Gastric acid secretion | hsa04971 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
|---|---|---|---|---|---|---|
| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 3 KEGG Pathways | + | ||||
| 1 | Calcium signaling pathway | |||||
| 2 | Neuroactive ligand-receptor interaction | |||||
| 3 | Gastric acid secretion | |||||
| Panther Pathway | [+] 2 Panther Pathways | + | ||||
| 1 | Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway | |||||
| 2 | Histamine H2 receptor mediated signaling pathway | |||||
| Pathwhiz Pathway | [+] 2 Pathwhiz Pathways | + | ||||
| 1 | Intracellular Signalling Through Histamine H2 Receptor and Histamine | |||||
| 2 | Gastric Acid Production | |||||
| Reactome | [+] 2 Reactome Pathways | + | ||||
| 1 | Histamine receptors | |||||
| 2 | G alpha (s) signalling events | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Monoamine GPCRs | |||||
| 2 | GPCRs, Class A Rhodopsin-like | |||||
| 3 | Secretion of Hydrochloric Acid in Parietal Cells | |||||
| 4 | GPCR ligand binding | |||||
| 5 | GPCR downstream signaling | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Histamine 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 2 | URL: 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 3 | Drug information of Betazole, 2008. eduDrugs. | |||||
| REF 4 | URL: 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 5 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 074151. | |||||
| REF 6 | URL: 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 7 | Clinical review of histamine2 receptor antagonists. Arch Intern Med. 1990 Apr;150(4):745-51. | |||||
| REF 8 | URL: 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 | FDA Approved Drug Products from FDA Official Website. 2009. Application Number: (ANDA) 075616. | |||||
| REF 10 | URL: 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 11 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001139) | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001852) | |||||
| REF 13 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002012) | |||||
| REF 14 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000641) | |||||
| REF 15 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001447) | |||||
| REF 16 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800000092) | |||||
| REF 17 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001137) | |||||
| REF 18 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002138) | |||||
| REF 19 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001448) | |||||
| REF 20 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001767) | |||||
| REF 21 | Effects 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 22 | Effect 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 23 | Characterization and modulation of antigen-induced effects in isolated rat heart. J Cardiovasc Pharmacol. 1991 Oct;18(4):556-65. | |||||
| REF 24 | Effect 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 25 | Analysis of Vancomycin in the Hindlimb Vascular Bed of the Rat. Am J Ther. 1996 Oct;3(10):681-687. | |||||
| REF 26 | Blastocyst H(2) receptor is the target for uterine histamine in implantation in the mouse. Development. 2000 Jun;127(12):2643-51. | |||||
| REF 27 | Pharmacological 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 28 | Afferent 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 29 | Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51. | |||||
| REF 30 | Does 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. | |||||
| REF 31 | Hemodynamic significance of histamine synthesis and histamine H1- and H2-receptor gene expression during endotoxemia. Naunyn Schmiedebergs Arch Pharmacol. 2002 Dec;366(6):513-21. | |||||
| REF 32 | Histamine 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 33 | 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. | |||||
| REF 34 | 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. | |||||
| REF 35 | Comparative pharmacology of epibatidine: a potent agonist for neuronal nicotinic acetylcholine receptors. Mol Pharmacol. 1995 Oct;48(4):774-82. | |||||
| REF 36 | 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. | |||||
| REF 37 | New and Future Drug Development for Gastroesophageal Reflux Disease. J Neurogastroenterol Motil. 2014 January; 20(1): 6-16. | |||||
| REF 38 | CP-66,948: an antisecretory histamine H2-receptor antagonist with mucosal protective properties. Dig Dis Sci. 1991 Dec;36(12):1721-8. | |||||
| REF 39 | Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015 | |||||
| REF 40 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800002138) | |||||
| REF 41 | Effects 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 42 | Conjugation 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 43 | Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31. | |||||
| REF 44 | 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 rec... J Med Chem. 2010 Sep 9;53(17):6386-97. | |||||
| REF 45 | N(G)-acylated aminothiazolylpropylguanidines as potent and selective histamine H(2) receptor agonists. ChemMedChem. 2009 Feb;4(2):232-40. | |||||
| REF 46 | Probing ligand-specific histamine H1- and H2-receptor conformations with NG-acylated Imidazolylpropylguanidines. J Pharmacol Exp Ther. 2006 Apr;317(1):139-46. | |||||
| REF 47 | Constitutive activity and structural instability of the wild-type human H2 receptor. J Neurochem. 1998 Aug;71(2):799-807. | |||||
| REF 48 | Heterologous expression of rat epitope-tagged histamine H2 receptors in insect Sf9 cells. Br J Pharmacol. 1997 Nov;122(5):867-74. | |||||
| REF 49 | Tiotidine, 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 50 | Fragment based design of new H4 receptor-ligands with anti-inflammatory properties in vivo. J Med Chem. 2008 Apr 24;51(8):2457-67. | |||||
| REF 51 | 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. | |||||
| REF 52 | G proteins of the Gq family couple the H2 histamine receptor to phospholipase C. Mol Endocrinol. 1996 Dec;10(12):1697-707. | |||||
| REF 53 | Structure determination of inactive-state GPCRs with a universal nanobody. Nat Struct Mol Biol. 2022 Dec;29(12):1188-1195. | |||||
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