Target Information

Target General Infomation
Target ID
T26500
Former ID
TTDR01193
Target Name
Histamine H4 receptor
Gene Name
HRH4
Synonyms
AXOR35; G protein-coupled receptor 105; GPCR105; GPRv53; H4 receptor; HH4R; SP9144; HRH4
Target Type
Clinical Trial
Disease Asthma [ICD10: J45]
Allergic rhinitis [ICD9: 472.0, 477, 995.3; ICD10: J00, J30, J31.0, T78.4]
Cognitive disorders [ICD9: 290-294, 294.0, 780.09, 780.9, 780.93; ICD10: F01-F07, F04, F05, R41.3]
Inflammatory disease [ICD9: 140-229, 147, 173, 573.3, 710-719; ICD10: C11, C44, K75.9, M00-M25]
Rheumatoid arthritis [ICD9: 710-719, 714; ICD10: M05-M06]
Function
The H4 subclass of histamine receptors could mediate the histamine signals in peripheral tissues. Displays a significant level of constitutive activity (spontaneous activity in the absence of agonist).
BioChemical Class
GPCR rhodopsin
Target Validation
T26500
UniProt ID
Q9H3N8
Sequence
MPDTNSTINLSLSTRVTLAFFMSLVAFAIMLGNALVILAFVVDKNLRHRSSYFFLNLAIS
DFFVGVISIPLYIPHTLFEWDFGKEICVFWLTTDYLLCTASVYNIVLISYDRYLSVSNAV
SYRTQHTGVLKIVTLMVAVWVLAFLVNGPMILVSESWKDEGSECEPGFFSEWYILAITSF
LEFVIPVILVAYFNMNIYWSLWKRDHLSRCQSHPGLTAVSSNICGHSFRGRLSSRRSLSA
STEVPASFHSERQRRKSSLMFSSRTKMNSNTIASKMGSFSQSDSVALHQREHVELLRARR
LAKSLAILLGVFAVCWAPYSLFTIVLSFYSSATGPKSVWYRIAFWLQWFNSFVNPLLYPL
CHKRFQKAFLKIFCIKKQPLPSQHSRSVSS
Drugs and Mode of Action
Drug(s) JNJ-38518168 Drug Info Phase 2 Rheumatoid arthritis [1]
UR-63325 Drug Info Phase 2 Allergic rhinitis [2]
PF-3893787 Drug Info Phase 1 Asthma [3]
Thioperamide Drug Info Terminated Cognitive disorders [4], [5]
Inhibitor (1H-indol-2-yl)(piperazin-1-yl)methanone Drug Info [6]
(R)-3-(1H-imidazol-4-yl)propyl sec-butylcarbamate Drug Info [7]
2-(2-(4-tert-Butylphenylthio)ethyl)-1H-imidazole Drug Info [8]
6-(4-Methylpiperazin-1-yl)-9H-purin-2-amine Drug Info [9]
6-(4-methylpiperazin-1-yl)-9Hpurine Drug Info [9]
6-(4-Methylpiperazin-1-yl)pyrimidine-2,4-diamine Drug Info [9]
9-benzyl-6-(4-methylpiperazin-1-yl)-9H-purine Drug Info [9]
A-846714 Drug Info [10]
A-943931 Drug Info [10]
IODOPHENPROPIT Drug Info [11]
JNJ-7777120 Drug Info [12]
Agonist (S)-alpha-methylhistamine Drug Info [13]
2-(3-bromophenyl)histamine Drug Info [14]
2-methylhistamine Drug Info [15]
4-methylhistamine Drug Info [15]
Clobenpropit Drug Info [16], [17]
HTMT Drug Info [18]
Imetit Drug Info [19], [20]
improgan Drug Info [18]
impromidine Drug Info [14]
N,N-dimethylhistamine Drug Info [15]
N-alpha-methyl histamine Drug Info [21]
N-ethylhistamine Drug Info [15]
N-methylhistamine Drug Info [22]
N-[3H]methylhistamine Drug Info [23]
UR-60427 Drug Info [24]
VUF 8430 Drug Info [25]
[3H](R)-alpha-methylhistamine Drug Info [23]
Antagonist burimamide Drug Info [22]
JNJ-10191584 Drug Info [26]
JNJ-38518168 Drug Info [27]
PF-3893787 Drug Info [3]
Thioperamide Drug Info [28], [29], [30]
UR-63325 Drug Info [31]
[3H]JNJ 7777120 Drug Info [32]
Target Expression Profile (TEP) and Drug Resistance Mutation (DRM)
TEP EXP Info
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Reactome Histamine receptors
G alpha (i) signalling events
WikiPathways GPCR ligand binding
GPCR downstream signaling
GPCRs, Other
References
REF 1ClinicalTrials.gov (NCT02295865) A Study to Evaluate Safety and Efficacy of Toreforant (JNJ-38518168) in Participants With Moderate to Severe Plaque-type Psoriasis. U.S. National Institutes of Health.
REF 2ClinicalTrials.gov (NCT01260753) Proof of Activity Study of UR-63325 in Allergic Rhinitis Induced by Nasal Challenge. U.S. National Institutes of Health.
REF 3Challenges of drug discovery in novel target space. The discovery and evaluation of PF-3893787: a novel histamine H4 receptor antagonist. Bioorg Med Chem Lett. 2011 Nov 1;21(21):6596-602.
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: 1267).
REF 5Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800004362)
REF 6J Med Chem. 2005 Dec 29;48(26):8289-98.Preparation and biological evaluation of indole, benzimidazole, and thienopyrrole piperazine carboxamides: potent human histamine h(4) antagonists.
REF 7Bioorg Med Chem Lett. 2009 Dec 1;19(23):6682-5. Epub 2009 Oct 6.Histamine H3 and H4 receptor affinity of branched 3-(1H-imidazol-4-yl)propyl N-alkylcarbamates.
REF 8Synthesis and structure-activity relationships of N-aryl-piperidine derivatives as potent (partial) agonists for human histamine H3 receptor. Bioorg Med Chem. 2010 Jul 15;18(14):5441-8. doi: 10.1016/j.bmc.2010.04.052. Epub 2010 Apr 21.
REF 9Bioorg Med Chem. 2009 Oct 15;17(20):7186-96. Epub 2009 Sep 2.2,4-Diaminopyrimidines as histamine H4 receptor ligands--Scaffold optimization and pharmacological characterization.
REF 10J Med Chem. 2008 Oct 23;51(20):6547-57. Epub 2008 Sep 26.Rotationally constrained 2,4-diamino-5,6-disubstituted pyrimidines: a new class of histamine H4 receptor antagonists with improved druglikeness and in vivo efficacy in pain and inflammation models.
REF 11J Med Chem. 2008 Jun 12;51(11):3145-53. Epub 2008 May 7.Discovery of novel human histamine H4 receptor ligands by large-scale structure-based virtual screening.
REF 12Bioorg Med Chem Lett. 2010 Apr 15;20(8):2516-9. Epub 2010 Mar 3.Identification and hit-to-lead exploration of a novel series of histamine H4 receptor inverse agonists.
REF 13Cloning and characterization of a novel human histamine receptor. J Pharmacol Exp Ther. 2001 Mar;296(3):1058-66.
REF 14Evaluation of histamine H1-, H2-, and H3-receptor ligands at the human histamine H4 receptor: identification of 4-methylhistamine as the first potent and selective H4 receptor agonist. J Pharmacol Exp Ther. 2005 Sep;314(3):1310-21. Epub 2005 Jun 9.
REF 15Compared pharmacology of human histamine H3 and H4 receptors: structure-activity relationships of histamine derivatives. Br J Pharmacol. 2006 Apr;147(7):744-54.
REF 16The histamine H4 receptor is functionally expressed on T(H)2 cells. J Allergy Clin Immunol. 2009 Mar;123(3):619-25.
REF 17Clobenpropit analogs as dual activity ligands for the histamine H3 and H4 receptors: synthesis, pharmacological evaluation, and cross-target QSAR studies. Bioorg Med Chem. 2009 Jun 1;17(11):3987-94. Epub 2009 Apr 11.
REF 18Cloning, expression, and pharmacological characterization of a novel human histamine receptor. Mol Pharmacol. 2001 Mar;59(3):434-41.
REF 19Histamine H4 receptor mediates eosinophil chemotaxis with cell shape change and adhesion molecule upregulation. Br J Pharmacol. 2004 May;142(1):161-71.
REF 20Histamine excites neonatal rat sympathetic preganglionic neurons in vitro via activation of H1 receptors. J Neurophysiol. 2006 Apr;95(4):2492-500. Epub 2005 Dec 14.
REF 21Histamine induces cytoskeletal changes in human eosinophils via the H(4) receptor. Br J Pharmacol. 2003 Nov;140(6):1117-27. Epub 2003 Oct 6.
REF 22Comparison of human, mouse, rat, and guinea pig histamine H4 receptors reveals substantial pharmacological species variation. J Pharmacol Exp Ther. 2001 Oct;299(1):121-30.
REF 23Cloning and pharmacological characterization of a fourth histamine receptor (H(4)) expressed in bone marrow. Mol Pharmacol. 2001 Mar;59(3):420-6.
REF 24(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. (Target id: 265).
REF 25Discovery of S-(2-guanidylethyl)-isothiourea (VUF 8430) as a potent nonimidazole histamine H4 receptor agonist. J Med Chem. 2006 Nov 16;49(23):6650-1.
REF 26Synthesis and structure-activity relationships of indole and benzimidazole piperazines as histamine H(4) receptor antagonists. Bioorg Med Chem Lett. 2004 Nov 1;14(21):5251-6.
REF 27The histamine H4 receptor: from orphan to the clinic. Front Pharmacol. 2015; 6: 65.
REF 28The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005 Feb;4(2):107-20.
REF 29Role of histamine H3 and H4 receptors in mechanical hyperalgesia following peripheral nerve injury. Neuroimmunomodulation. 2007;14(6):317-25. Epub 2008 Apr 10.
REF 30Role of histamine in short- and long-term effects of methamphetamine on the developing mouse brain. J Neurochem. 2008 Nov;107(4):976-86. Epub 2008 Sep 11.
REF 31Azines as histamine H4 receptor antagonists. Front Biosci (Schol Ed). 2012 Jan 1;4:967-87.
REF 32A potent and selective histamine H4 receptor antagonist with anti-inflammatory properties. J Pharmacol Exp Ther. 2004 Apr;309(1):404-13. Epub 2004 Jan 13.

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