Target Validation Information
TTD ID T77913
Target Name Histamine H1 receptor (H1R)
Type of Target
Successful
Drug Potency against Target Antazoline Drug Info IC50 = 38.4 nM/L [13]
Azatadine Drug Info IC50 = 40000 nM
Azelastine Drug Info IC50 = 4000 nM/L [18]
Bepotastine Drug Info IC50 = 101 nM
Cetirizine Drug Info Ki = 6 nM [14]
Chlorpheniramine Drug Info IC50 = 36 nM [20]
Cinnarizine Drug Info IC50 = 1870 nM [20]
Cyclizine Drug Info IC50 = 5420 nM [20]
Diphenhydramine Drug Info IC50 = 1460 nM [20]
Emedastine Drug Info Ki = 1.3 nM [23]
Epinastine Drug Info IC50 = 30000 nM [24]
Ergotidine Drug Info Ki = 10 nM [16]
Ketotifen Drug Info IC50 = 52 nM [20]
Loratadine Drug Info IC50 = 50 nM/l [22]
Mepyramine Drug Info IC50 = 855000 nM [20]
Olopatadine Drug Info Ki = 31.6 nM [25]
Oxatomide Drug Info IC50 = 4.5 nM [20]
Pheniramine Drug Info IC50 = 33.9 nM/L [13]
Promethazine Drug Info IC50 = 340 nM [20]
Terfenadine Drug Info IC50 = 200 nM/l [21]
Tranilast Drug Info IC50 = 100000 nM [17]
Trimeprazine Drug Info IC50 = 19 nM [20]
Triprolidine Drug Info IC50 = 5.74 nM
Carebastine Drug Info IC50 = 0.17 nM/ml [26]
1-(4-p-Tolyl-butyl)-piperidine Drug Info Ki = 3200 nM [6]
2-(9,10-dihydroanthracen-9-yl)-N-methylethanamine Drug Info Ki = 48 nM [8]
3,3-diphenylpropan-1-amine Drug Info Ki = 2758 nM [8]
4,4-Diphenylbutan-1-amine Drug Info Ki = 1670 nM [8]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one Drug Info Ki = 610 nM [11]
9-(2-aminoethyl)-9,10-dihydroanthracene Drug Info Ki = 137 nM [8]
9-(2-aminopropyl)-9,10-dihydroanthracene Drug Info Ki = 175 nM [8]
9-(Aminomethyl)-9,10-dihydroanthracene Drug Info Ki = 197 nM [8]
9-Phenyl-2,3-dihydro-1H-indeno[2,1-c]pyridine Drug Info IC50 = 53 nM [1]
AR-129330 Drug Info IC50 = 150 nM [9]
DIMEBOLIN Drug Info IC50 = 158 nM [10]
Diphenyl(piperidin-4-yl)methanol Drug Info Ki = 659 nM [6]
KF-A6 Drug Info IC50 = 3600 nM [5]
MDL-28163 Drug Info IC50 = 59 nM [3]
N,N-dimethyl-2,2-diphenylethanamine Drug Info Ki = 5172 nM [8]
N,N-Dimethyl-3,3-diphenylpropan-1-amine Drug Info Ki = 75 nM [8]
N,N-dimethyl-4,4-diphenylbutan-1-amine Drug Info Ki = 70 nM [8]
N-methyl-3,3-diphenylpropan-1-amine Drug Info Ki = 64 nM [8]
N-methyl-4,4-diphenylbutan-1-amine Drug Info Ki = 386 nM [8]
OCTOCLOTHEPIN Drug Info Ki = 0.19 nM [12]
PegCNTF Drug Info IC50 = 100 nM [3]
R-226161 Drug Info Ki = 74 nM [4]
R-dimethindene Drug Info Ki = 0.4 nM [7]
RUPATADINE Drug Info IC50 = 3.9 nM [3]
Action against Disease Model Acrivastine Drug Info Constitutive H1 receptor activity (inverse agonism) as measured by inhibition of basal l uMinescence in COShuH1 cells, IC50: 40 nM [2]
Bromodiphenhydramine Drug Info Inhibition of [3H]mepyramine binding in rat brain Ki: 13.0 nM
Carbinoxamine Drug Info Inhibition of [3H]mepyramine binding in rat brain Ki: 2.3 nM
Cyproheptadine Drug Info The aim of this study is to find a relationship between serotonin (5-HT) and its metabolite 5-hydroxy indol acetic acid (5-HIAA) in hippocampus, frontal neocortex and platelets.Serotonin and 5-HIAA were measured in cultured neurons and compared with those produced by h uMan platelets. The cortical neuronal 5-HIAA/serotonin ratio was 4.7 and for hippocampal neurons it was 3.2. In h uMan platelets, this ratio was 1.35 suggesting that the highest serotonin metabolism occurs in the frontal neocortex followed by the hippocampus and platelets. In the presence of 0.3 microM ofp-chlorophenylalanine both cultured neurons and platelets exhibited an approximately 50% decrease in serotonin and 5-HIAA concentration suggesting similarities in the metabolic profile in both preparations. In addition, we found that serotonin by itself does not play any role in platelet aggregation but potentiates this phenomenon in the presence of calci uM ionophore A23187. This synergistic interaction between serotonin (2-5 microM) and A23187 (0.5-2 microM) was inhibited by serotonin receptor blockers [methysergide (IC50 = 18 microM) and cyproheptadine (IC50, 20 microM)] and calci uM channel blockers (verapamil and diltiazem, IC50 = 20 and 40 microM, respectively) that indicate both mechanisms are receptor mediated. Similarly, U73122, an inhibitor of phospholipase C (PLC), blocked the synergistic effect of serotonin and ionophore at an IC50 value of 9.2 microM. Wortmannin, a phosphoinositide 3-kinase (PI 3-K) inhibitor, also blocked the response (IC50 = 2.6 microM) by inhibiting respiratory burst. However, neither genistein, a tyrosine-specific protein kinase inhibitor, nor chelerythrine, a protein kinase C (PKC) inhibitor, affected aggregation. Our results are strongly suggestive of a synergistic interaction between serotonin type-2 and Ca-ionophore via a PLC/Ca signalling pathway. [15]
Dimethindene Drug Info Inhibition of [3H]mepyramine binding in rat brain Ki: 8.0 nM
Diphenylpyraline Drug Info Inhibition of [3H]mepyramine binding in rat brain Ki: 3.2 nM
Doxepin Drug Info binding to guinea-pig brain(Cerebral cortex) Ka :1.7x10(10) [19]
Mequitazine Drug Info binding of [???H]mepyramine to guinea pig lung IC50: 1 nM
Methdilazine Drug Info Inhibition of [3H]mepyramine binding in rat brain Ki: 2.3 nM
Mizolastine Drug Info inhibited with high affinity the binding of [3H]pyrilamine to histamine H1 receptors in guinea pig cerebellar membranes and sections. IC50: 47 nM/L [22]
Phenindamine Drug Info Inhibition of [3H]mepyramine binding in rat brain Ki: 20.0 nM
Tranilast Drug Info IC50 on vascular endotheli uM growth factor-induced chemotaxis in h uMan dermal microvascular endothelial cells: 135000nM,
References
REF 1 Conformationally-restricted ligands for the histamine H1 receptor. Bioorg Med Chem Lett. 2000 Jun 5;10(11):1277-9.
REF 2 A novel phenylaminotetralin radioligand reveals a subpopulation of histamine H(1) receptors. J Pharmacol Exp Ther. 2002 Jul;302(1):328-36.
REF 3 Designed multiple ligands. An emerging drug discovery paradigm. J Med Chem. 2005 Oct 20;48(21):6523-43.
REF 4 Tricyclic isoxazolines: identification of R226161 as a potential new antidepressant that combines potent serotonin reuptake inhibition and alpha2-a... Bioorg Med Chem. 2007 Jun 1;15(11):3649-60.
REF 5 Design, synthesis, and evaluation of 10-N-substituted acridones as novel chemosensitizers in Plasmodium falciparum. Antimicrob Agents Chemother. 2007 Nov;51(11):4133-40.
REF 6 Structural determinants for histamine H(1) affinity, hERG affinity and QTc prolongation in a series of terfenadine analogs. Bioorg Med Chem Lett. 2009 Sep 1;19(17):5043-7.
REF 7 Characterization of novel selective H1-antihistamines for clinical evaluation in the treatment of insomnia. J Med Chem. 2009 Sep 10;52(17):5307-10.
REF 8 Synthesis, structure-affinity relationships, and modeling of AMDA analogs at 5-HT2A and H1 receptors: structural factors contributing to selectivity. Bioorg Med Chem. 2009 Sep 15;17(18):6496-504.
REF 9 Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: in vitro profiling and in vivo evaluation. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6166-71.
REF 10 Synthesis and biological activity of 5-styryl and 5-phenethyl-substituted 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indoles. Bioorg Med Chem Lett. 2010 Jan 1;20(1):78-82.
REF 11 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 12 Exploring the neuroleptic substituent in octoclothepin: potential ligands for positron emission tomography with subnanomolar affinity for (1)-adre... J Med Chem. 2010 Oct 14;53(19):7021-34.
REF 13 Inhibition of histamine-induced human conjunctival epithelial cell responses by ocular allergy drugs. Arch Ophthalmol. 1999 May;117(5):643-7.
REF 14 Binding characteristics of cetirizine and levocetirizine to human H(1) histamine receptors: contribution of Lys(191) and Thr(194). Mol Pharmacol. 2002 Feb;61(2):391-9.
REF 15 The metabolism of serotonin in neuronal cells in culture and platelets. Exp Brain Res. 2007 Nov;183(3):411-6.
REF 16 Major advances in the development of histamine H4 receptor ligands. Drug Discov Today. 2009 Aug;14(15-16):745-53.
REF 17 Mechanism of inhibitory action of tranilast on the release of slow reacting substance of anaphylaxis (SRS-A) in vitro: effect of tranilast on the release of arachidonic acid and its metabolites. Jpn J Pharmacol. 1988 Jan;46(1):53-60.
REF 18 The interaction of azelastine with human lung histamine H1, beta, and muscarinic receptor-binding sites. J Allergy Clin Immunol. 1989 Apr;83(4):771-6.
REF 19 The binding of doxepin to histamine H1-receptors in guinea-pig and rat brain. Br J Pharmacol. 1985 Feb;84(2):417-24.
REF 20 Inhibition of histamine release from human lung in vitro by antihistamines and related drugs. Br J Pharmacol. 1980 Aug;69(4):663-7.
REF 21 Absence of an effect of terfenadine on guinea pig brain histamine H1-receptors in vivo determined by receptor binding techniques. Arzneimittelforschung. 1982;32(9a):1167-70.
REF 22 In vivo and in vitro interaction of the novel selective histamine H1 receptor antagonist mizolastine with H1 receptors in the rodent. Arzneimittelforschung. 1995 May;45(5):551-8.
REF 23 Emedastine: a potent, high affinity histamine H1-receptor-selective antagonist for ocular use: receptor binding and second messenger studies. J Ocul Pharmacol. 1994 Winter;10(4):653-64.
REF 24 Comparison of anti-allergic activities of the histamine H1 receptor antagonists epinastine, ketotifen and oxatomide in human leukocytes. Arzneimittelforschung. 1995 Jan;45(1):36-40.
REF 25 Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL-4943A), a novel drug for treating ocular allergic diseases. J Pharmacol Exp Ther. 1996 Sep;278(3):1252-61.
REF 26 Towards the optimal antihistamine: studies with ebastine. Inflamm Res. 1998;47 Suppl 1:S36-7.

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