Therapeutic Targets Database
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TTD Target ID: TTDC00079

Target Information
NameHistamine H3 receptor    
Type of targetClinical trial target    
SynonymsG protein-coupled receptor 97    
HH3R    
Histamine receptor 3    
DiseaseAcid-related diseases
[ICD9: 531-534   ICD10: K25-K27]
[1]
Allergic rhinitis, unspecified
[ICD9: 472.0, 477, 995.3   ICD10: J00, J30, J31.0, T78.4]
[2]
Alzheimer's disease
[ICD9: 331.0   ICD10: G30]
[3][4]
Attention-deficit hyperactivity disorder
[ICD9: 314.0   ICD10: F90]
[5]
Central nervous system diseases
[ICD9: 294.1, 307.23, 314.00, 314.01, 320-322, 323, 331.0, 332, 333.4, 340, 344.1, 344.81, 348.0   ICD10: A83-A86, B94.1, F02.2, F02.3, F90, F95.2, G00-G37, G83.5, G93.0]
[1]
Inflammatory diseases[1]
Schizophrenia
[ICD9: 295   ICD10: F20]
[3][4]
Drug(s)239512Phase IIMultiple sclerosis
ABT-652Phase IIDiabetic neuropathy
AZD5213Phase IIAlzheimer's disease
GSK239512Phase IIMild to Moderate Alzheimers Disease, Dementia[6]
ABT-652Phase I completedExcessive daytime sleepiness
AZD5213Phase IADHD
HPP404Phase IAllergic rhinitis[7]
SAR110894Phase IAlzheimer's[8]
ABT-239Terminated in Phase IAlzheimer's disease and schizophrenia[3][4][9]
CipralisantSuspended in Phase IIAttention-deficit hyperactivity disorder[5]
GSK1004723Suspended in Phase II in GSK 2009 ReportAllergic rhinitis[6]
GSK835726Suspended in Phase II in GSK 2009 ReportAllergic rhinitis[6]
BioChemical ClassG-protein coupled receptor (rhodopsin family)    
PathwayNeuroactive ligand-receptor interaction
UniProt IDQ9Y5N1
FunctionThe h3 subclass of histamine receptors could mediate the histamine signals in cns and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist).    
SequenceMERAPPDGPLNASGALAGEAAAAGGARGFSAAWTAVLAALMALLIVATVLGNALVMLAFV ADSSLRTQNNFFLLNLAISDFLVGAFCIPLYVPYVLTGRWTFGRGLCKLWLVVDYLLCTS SAFNIVLISYDRFLSVTRAVSYRAQQGDTRRAVRKMLLVWVLAFLLYGPAILSWEYLSGG SSIPEGHCYAEFFYNWYFLITASTLEFFTPFLSVTFFNLSIYLNIQRRTRLRLDGAREAA GPEPPPEAQPSPPPPPGCWGCWQKGHGEAMPLHRYGVGEAAVGAEAGEATLGGGGGGGSV ASPTSSSGSSSRGTERPRSLKRGSKPSASSASLEKRMKMVSQSFTQRFRLSRDRKVAKSL AVIVSIFGLCWAPYTLLMIIRAACHGHCVPDYWYETSFWLLWANSAVNPVLYPLCHHSFR RAFTKLLCPQKLKIQPHSSLEHCWK
Related US Patent6,436,939
6,506,756
6,518,287
6,528,522
6,559,140
Target ValidationClick to Find Target Validation Information.    
QSAR ModelClick to Find Target QSAR Model.    
Inhibitor (1H-indol-2-yl)[10]
(1R,2R)-2-[11]
(1R,2S)-2-[11]
(1S,2S)-2-[11]
(R)-1-[12]
(R)-1-[12]
(R)-1-[12]
(R)-1-[12]
(R)-2-[11]
(R)-2-[12]
(R)-2-[12]
(R)-2-methyl-1-[12]
(R)-2-methyl-1-[12]
(R)-3-[13]
(R)-3-[12]
(R)-4-[12]
(R)-6-[14]
(S)-1-[12]
(S)-1-[12]
(S)-1-[12]
(S)-1-[12]
(S)-2-[12]
(S)-2-[12]
(S)-2-methyl-1-[12]
(S)-2-methyl-1-[12]
(S)-3-[13]
(S)-4-[12]
1- (2-[12]
1- (2-m-tolyl-ethyl)-pyrrolidine[12]
1- (2-methoxyphenethyl)pyrrolidine[12]
1- (2-p-tolyl-ethyl)-pyrrolidine[12]
1- (3-[15]
1- (3-[16]
1- (3-[17]
1- (3-[17]
1- (3-methoxyphenethyl)pyrrolidine[12]
1- (4-[12]
1- (4-methoxyphenethyl)pyrrolidine[12]
1- (4-nitrophenethyl)pyrrolidine[12]
1-[2- (2,4,6-trimethyl-phenyl)-ethyl]-pyrrolidine[12]
2- ([18]
2- ([19]
2- (1,4'-bipiperidin-1'-yl)thiazolo[4,5-b]pyridine[20]
2- (1,4'-bipiperidin-1'-yl)thiazolo[4,5-c]pyridine[20]
2- (1H-Imidazol-4-yl)-cyclopropylamine[21]
2- (1H-Imidazol-4-yl)-cyclopropylamine[21]
2- (2-[12]
2- (2-[12]
2- (2-[12]
2- (3-Methyl-3H-imidazol-4-yl)-ethylamine[22]
2- (4-Cyclopentyl-piperazin-1-yl)-quinoline[23]
2- (4-Cyclopropyl-piperazin-1-yl)-quinoline[23]
2- (4-Isopropyl-piperazin-1-yl)-quinoline[23]
2- (4-Methyl-piperazin-1-yl)-quinoline[23]
2- (4-Propyl-piperazin-1-yl)-quinoline[23]
2- (ethoxycarbonyl)-1H-indole-5-carboxylic acid[24]
2-[2- (1H-Imidazol-4-yl)-cyclopropyl]-ethylamine[21]
2-[2- (1H-Imidazol-4-yl)-cyclopropyl]-ethylamine[21]
2-[4- (1-Ethyl-propyl)-piperazin-1-yl]-quinoline[23]
3- ([18]
4- ([25]
4- ([26]
4- ([11]
4- ([11]
4- (2-[27]
4- (2-[27]
4- (2-[27]
4- (2-[27]
4- (2-[27]
4- (2-[27]
4- (2-[18]
4- (2-[27]
4- (2-[27]
4- (2-[12]
4- (3-Phenoxy-propyl)-1H-imidazole[28]
4- (4-Phenyl-butyl)-1H-imidazole[28]
4- (4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one[29]
4- (6-Cyclohexyl-hex-3-ynyl)-1H-imidazole[22]
4- (6-Cyclopentyl-hex-3-ynyl)-1H-imidazole[22]
4- (7,7-Dimethyl-oct-3-ynyl)-1H-imidazole[22]
4- (7-Methyl-oct-3-ynyl)-1H-imidazole[22]
4- (8-Phenyl-oct-3-ynyl)-1H-imidazole[22]
4-Benzyl-1-[3-phenylpropoxy)propyl]piperidine[16]
4-Butyl-1-[3- (phenylpropoxy)propyl]piperidine[16]
4-Hept-3-ynyl-1H-imidazole[22]
4-Hex-3-ynyl-1H-imidazole[22]
4-Propyl-1-[3- (phenylpropoxy)propyl]piperidine[16]
4-[3- (4-Butyl-phenoxy)-propyl]-1H-imidazole[30]
4-[3- (4-Ethynyl-phenoxy)-propyl]-1H-imidazole[30]
4-[3- (4-Methoxy-phenoxy)-propyl]-1H-imidazole[28]
4-isopropyl-2- (phenoxymethyl)morpholine[19]
5- (2-[12]
5-ethyl-2- (2-[12]
5-methoxy-2- (2-[12]
5-phenyl-2- (4-[31]
A-349821[32]
APLYSAMINE[33]
C-[2- (1H-Imidazol-4-yl)-cyclopropyl]-methylamine[21]
C-[2- (1H-Imidazol-4-yl)-cyclopropyl]-methylamine[21]
C-[2- (1H-Imidazol-4-yl)-cyclopropyl]-methylamine[21]
C-[2- (1H-Imidazol-4-yl)-cyclopropyl]-methylamine[21]
CARCININE[33]
CONESSINE[34]
GR-175737[22]
GSK-189254[35]
GT-2016[22]
IODOPROXYFAN[28]
JNJ-28583867[36]
JNJ-7777120[10]
N-alpha-methylhistamine[37]
N-benzyl-4-cyclopentylpiperazine-1-carboxamide[38]
N-methyl-2- (pyridin-2-yl)ethanamine[24]
ST-1025[31]
ST-1093[31]
TIPROLISANT[15]
UCL-1972[39]
UCL-2138[17]
VERONGAMINE[40]
VUF-10214[41]
VUF-5296[21]
VUF-5297[21]
aerophobin-1[40]
des-bromoaplysamine-1[42]
Agonist (R)-alpha-methylhistamine[9][1]
Imetit[9]
Immepip[9]
Immethridine[9]
Methimepip[9]
AntagonistA-317920[9]
A-331440[9]
ABT-239[3][4][9]
Ciproxifan[9]
Clobenpropit[9][2]
FUB 649[9]
GSK1004723[6]
GSK189254A[9]
GSK239512[6]
GSK835726[6]
HPP404[7]
JNJ-10181457[9]
JNJ-5207852[9]
NNC 0038-0000-1202[9]
Proxyfan[9]
SAR110894[8]
SCH79687[9]
Thioperamide[9][2]
UCL-1390[43]
UCL1972[9]
VUF 5681[9]
VUF5391[9]
LigandCipralisant[5]
MultitargetGSK1004723[6]
GSK835726[6]
Cross References 3D Structure
Related Literature
On-Line Medical Dictionary
Ref 1Azomethine prodrugs of (R)-alpha-methylhistamine, a highly potent and selective histamine H3-receptor agonist. Curr Med Chem. 2001 Sep;8(11):1329-40. To Reference
Ref 2Combined histamine H1 and H3 receptor blockade produces nasal decongestion in an experimental model of nasal congestion. Am J Rhinol. 1999 Sep-Oct;13(5):391-9. To Reference
Ref 3Use of the H3 receptor antagonist radioligand [3H]-A-349821 to reveal in vivo receptor occupancy of cognition enhancing H3 receptor antagonists. Br J Pharmacol. 2009 May;157(1):139-49. To Reference
Ref 4A robust and high-capacity [(35)S]GTPgammaS binding assay for determining antagonist and inverse agonist pharmacological parameters of histamine H(3) receptor ligands. Assay Drug Dev Technol. 2008 Jun;6(3):339-49. To Reference
Ref 5J Pharmacol Exp Ther. 2005 Jul;314(1):271-81. Epub 2005 Apr 8.G protein-dependent pharmacology of histamine H3 receptor ligands: evidence for heterogeneous active state receptor conformations. To Reference
Ref 6GSK. Product Development Pipeline. February 2009. To Reference
Ref 72011 Pipeline of TransTech Pharma. To Reference
Ref 8Pharma & Vaccines. Product Development Pipeline. April 29 2009. To Reference
Ref 9The histamine H3 receptor: from gene cloning to H3 receptor drugs. Nat Rev Drug Discov. 2005 Feb;4(2):107-20. To Reference
Ref 10J 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. To Reference
Ref 11J Med Chem. 1995 May 12;38(10):1593-9.A novel pyrrolidine analog of histamine as a potent, highly selective histamine H3 receptor agonist. To Reference
Ref 12Bioorg Med Chem Lett. 2008 Jan 1;18(1):355-9. Epub 2007 Oct 24.In vitro SAR of pyrrolidine-containing histamine H3 receptor antagonists: trends across multiple chemical series. To Reference
Ref 13Bioorg 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. To Reference
Ref 14Bioorg Med Chem Lett. 2010 Jun 1;20(11):3295-300. Epub 2010 Apr 18.In vitro studies on a class of quinoline containing histamine H3 antagonists. To Reference
Ref 15Bioorg Med Chem. 2009 Apr 15;17(8):3037-42. Epub 2009 Mar 14.Diether derivatives of homo- or substituted piperidines as non-imidazole histamine H3 receptor ligands. To Reference
Ref 16Bioorg Med Chem. 2008 Sep 15;16(18):8729-36. Epub 2008 Jul 29.Piperidine variations in search for non-imidazole histamine H(3) receptor ligands. To Reference
Ref 17Bioorg Med Chem Lett. 2009 Apr 15;19(8):2172-5. Epub 2009 Mar 3.Fluorinated non-imidazole histamine H3 receptor antagonists. To Reference
Ref 18J Med Chem. 2010 Sep 9;53(17):6445-56.Investigation of the histamine H3 receptor binding site. Design and synthesis of hybrid agonists with a lipophilic side chain. To Reference
Ref 19Bioorg Med Chem Lett. 2008 Nov 1;18(21):5796-9. Epub 2008 Sep 24.2-Aryloxymethylmorpholine histamine H(3) antagonists. To Reference
Ref 20Bioorg Med Chem Lett. 2009 Nov 1;19(21):6176-80. Epub 2009 Sep 6.Synthesis and structure-activity relationships of 2-(1,4'-bipiperidin-1'-yl)thiazolopyridine as H3 receptor antagonists. To Reference
Ref 21J Med Chem. 2003 May 8;46(10):1980-8.Cyclopropane-based conformational restriction of histamine. (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure. To Reference
Ref 22Bioorg Med Chem Lett. 1998 May 19;8(10):1133-8.New acetylene based histamine H3 receptor antagonists derived from the marine natural product verongamine. To Reference
Ref 23J Med Chem. 2005 Jan 13;48(1):306-11.2-(4-alkylpiperazin-1-yl)quinolines as a new class of imidazole-free histamine H3 receptor antagonists. To Reference
Ref 24J Med Chem. 2009 Jul 9;52(13):3855-68.5-hydroxyindole-2-carboxylic acid amides: novel histamine-3 receptor inverse agonists for the treatment of obesity. To Reference
Ref 25Bioorg. Med. Chem. 18(14):5441-5448 (2010) To Reference
Ref 26Bioorg Med Chem Lett. 2006 Jan 15;16(2):395-9. Epub 2005 Oct 21.Novel histamine H3 receptor antagonists based on the 4-[(1H-imidazol-4-yl)methyl]piperidine scaffold. To Reference
Ref 27J Med Chem. 2010 May 13;53(9):3840-4.Role of hydrophobic substituents on the terminal nitrogen of histamine in receptor binding and agonist activity: development of an orally active histamine type 3 receptor agonist and evaluation of its antistress activity in mice. To Reference
Ref 28Bioorg Med Chem Lett. 2001 Apr 9;11(7):951-4.Different antagonist binding properties of human and rat histamine H3 receptors. To Reference
Ref 29J 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. To Reference
Ref 30Bioorg Med Chem Lett. 2000 Oct 16;10(20):2379-82.Analogues and derivatives of ciproxifan, a novel prototype for generating potent histamine H3-receptor antagonists. To Reference
Ref 31Bioorg Med Chem Lett. 2010 Oct 1;20(19):5883-6. Epub 2010 Aug 1.Azole derivatives as histamine H3 receptor antagonists, part 2: C-C and C-S coupled heterocycles. To Reference
Ref 32Bioorg Med Chem Lett. 2008 Aug 1;18(15):4377-9. Epub 2008 Jun 21.Refinement of histamine H3 ligands pharmacophore model leads to a new class of potent and selective naphthalene inverse agonists. To Reference
Ref 33J Med Chem. 2008 Sep 11;51(17):5423-30. Epub 2008 Aug 7.The alkaloid conessine and analogues as potent histamine H3 receptor antagonists. To Reference
Ref 34J Med Chem. 2009 Aug 13;52(15):4640-9.Design of a new histamine H3 receptor antagonist chemotype: (3aR,6aR)-5-alkyl-1-aryl-octahydropyrrolo[3,4-b]pyrroles, synthesis, and structure-activity relationships. To Reference
Ref 35J Med Chem. 2010 Nov 11;53(21):7869-73.Diaryldiamines with dual inhibition of the histamine H(3) receptor and the norepinephrine transporter and the efficacy of 4-(3-(methylamino)-1-phenylpropyl)-6-(2-(pyrrolidin-1-yl)ethoxy)naphthalen-1-ol in pain. To Reference
Ref 36Bioorg Med Chem Lett. 2008 Jan 1;18(1):39-43. Epub 2007 Nov 13.Synthesis and biological activity of piperazine and diazepane amides that are histamine H3 antagonists and serotonin reuptake inhibitors. To Reference
Ref 37Bioorg Med Chem Lett. 2009 Aug 1;19(15):4075-8. Epub 2009 Jun 13.Development of a selective and potent radioactive ligand for histamine H(3) receptors: A compound potentially useful for receptor occupancy studies. To Reference
Ref 38Bioorg Med Chem Lett. 2006 Oct 15;16(20):5303-8.Ureas with histamine H3-antagonist receptor activity--a new scaffold discovered by lead-hopping from cinnamic acid amides. To Reference
Ref 39Bioorg Med Chem Lett. 2009 Feb 1;19(3):903-7. Epub 2008 Dec 6.Novel imidazole-based histamine H3 antagonists. To Reference
Ref 40J. Nat. Prod. 57(1):175-177 (1994) To Reference
Ref 41J 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. To Reference
Ref 42Bioorg Med Chem Lett. 2006 Feb 15;16(4):897-900. Epub 2005 Nov 21.Aplysamine-1 and related analogs as histamine H3 receptor antagonists. To Reference
Ref 43Emerging drugs for eating disorder treatment. Expert Opin Emerg Drugs. 2006 May;11(2):315-36. To Reference



 

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Professor in Department of Pharmacy
National University of Singapore, Singapore


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