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Histamine H3 Receptors (histamine + h3_receptor)

Distribution by Scientific Domains

Medical Sciences	63%
Chemistry	27%

Terms modified by Histamine H3 Receptors

histamine h3 receptor antagonist

Selected Abstracts

Synthesis and Stability in Biological Media of 1H -Imidazole-1-carboxylates of ROS203, an Antagonist of the Histamine H3 Receptor

CHEMISTRY & BIODIVERSITY, Issue 1 2008
Mirko Rivara
Abstract A series of carbamate derivatives of the H3 antagonist ROS203 (1) were prepared, and their lipophilicity and steric hindrance were modulated by introducing linear or branched alkyl chains of various lengths. In vitro stability studies were conducted to evaluate how structural modulations affect the intrinsic reactivity of the carbamoyl moiety and its recognition by metabolic enzymes. Linear alkyl carbamates were the most susceptible to enzymatic hydrolysis, with bioconversion rates being higher in rat liver and plasma. Chain ramification significantly enhanced the enzymatic stability of the set, with two derivatives (1g and 1h) being more stable by a factor of 8,40 than the ethyl carbamate 1a. Incubation with bovine serum albumin (BSA) showed a protective role of proteins on chemical and porcine-liver esterase (PLE)-catalyzed hydrolysis. Ex vivo binding data after i.v. administration of 1h revealed prolonged displacement of the labeled ligand [3H]-(R)- , -methylhistamine ([3H]RAMHA) from rat-brain cortical membranes, when compared to 1. However, the high rates of bioconversion in liver, as well as the chemical instability of 1h, suggest that further work is needed to optimize the enzymatic and chemical stability of these compounds. [source]

Discovery of a New Class of Non-imidazole Oxazoline-Based Histamine H3 Receptor (H3R) Inverse Agonists

CHEMMEDCHEM, Issue 7 2009
Sylvain Célanire Dr.
Abstract H3R inverse agonists based on an aminopropoxy-phenyloxazoline framework constitute highly valuable druglike lead compounds that display efficacy in a mouse model of recognition memory. [source]

Nasal Allergic Response Mediated by Histamine H3 Receptors in Murine Allergic Rhinitis

THE LARYNGOSCOPE, Issue 10 2005
Muneo Nakaya MD
Abstract Background: Histamine is one of the most important chemical mediators causing nasal allergic symptoms, and H1 receptor antagonist have been used as the treatment first choice in nasal allergy. The presence of H3 receptors has also been determined in the human nasal mucosa, but few studies have investigated the involvement of H3 receptors in nasal allergy. Objective: We used a murine allergic model to investigate the presence of nasal mucosa H3 receptor mRNA and any H3 receptor agonist or antagonist influences on clinical nasal allergic symptoms. Methods: H3 receptor mRNA in nasal mucosa was investigated by reverse-transcription polymerase chain reaction. OVA-sensitized mice were given an intraperitoneal injection of H3 receptor agonist or antagonist, and clinical nasal allergic symptoms were scored over 10 minutes after nasal provocation of OVA. Inhibition of nasal allergic symptoms was also examined using an H1 receptor antagonist alone and using a both an H3 receptor agonist and an H1 receptor antagonist. Results: H3 receptor mRNA was identified in the murine nasal mucosa. The H3 receptor agonist (R)-,-metylhistamine significantly inhibited clinical nasal allergic symptoms of OVA-sensitized mice. The H3 receptor agonist and H1 receptor antagonist inhibited clinical nasal allergic symptoms in the murine allergic model more strongly than the single drug. Conclusion: The foregoing results indicate that H3 receptors are involved in modulation of nasal allergy. H3 receptor agonists can also be useful as a novel therapeutic approach in nasal allergy. Both H3 receptor agonist and H1 receptor antagonist may be more effective than a single drug. [source]

Conformational analysis for some nonclassical antagonists of histamine H3 receptor

INTERNATIONAL JOURNAL OF QUANTUM CHEMISTRY, Issue 8 2007
Ana Borota
Abstract A conformational search in vacuum for a series of 1,3-substituted pyrrolidine derivatives has been performed using the AMBER, AM1, PM3, and MNDO methods. Conformational analysis of the pyrrolidine ligands suggests that these compounds could have many conformers that populate the low-energy minima on the potential energy surface (PES). The conformational space occupied by the ligands is large and, in vacuum, the rotation barriers of different flexible bonds have energies between 0.5 and thousands of kcal/mol. By optimization, most conformers have energy barriers of 0,5 kcal/mol; thus, they could interconvert easily to obtain better interactions in the receptor active site. Optimized conformers having energy barriers of >5 kcal/mol display bad geometries with very large bond lengths and deformed rings. Shapes and heights of rotation barriers obtained through COSMO,AM1 single-point calculations in water are similar to those obtained from single-point calculations in vacuum. However, in water the energy barriers are lower, allowing most conformers to convert in other low-energy conformers. The best conformers in vacuum and in water are different: the gas phase best conformer has a helical shape, while the best conformer in water has an extended shape. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007 [source]

Pharmacological effects of carcinine on histaminergic neurons in the brain

BRITISH JOURNAL OF PHARMACOLOGY, Issue 5 2004
Zhong Chen
Carcinine (, -alanyl histamine) is an imidazole dipeptide. The present study was designed to characterize the pharmacological effects of carcinine on histaminergic activity in the brain and on certain neurobehavior. Carcinine was highly selective for the histamine H3 receptor over H1 or H2 receptor (Ki (,M)=0.2939±0.2188 vs 3621.2±583.9 or 365.3±232.8 ,M, respectively). Carcinine at a dose of 20 mg kg,1 slightly increased histidine decarboxylase (HDC) activity in the cortex (from 0.186±0.069 to 0.227±0.009 pmol mg protein,1 min,1). In addition, carcinine (10, 20, and 50 mg kg,1) significantly decreased histamine levels in mice brain. Like thioperamide, a histamine H3 receptor antagonist, carcinine (20, 50 ,M) significantly increased 5-HT release from mice cortex slices, but had no apparent effect on dopamine release. Carcinine (20 mg kg,1) significantly inhibited pentylenetetrazole-induced kindling. This inhibition was completedly reversed by (R)- , -methylhistamine, a representative H3 receptor agonist, and , -fluromethylhistidine, a selective HDC inhibitor. Carcinine (20 mg kg,1) ameliorated the learning deficit induced by scopolamine. This amelioration was reversed by (R)- , -methylhistamine as evaluated by the passive avoidance test in mice. Like thioperamide, carcinine dose-dependently increased mice locomotor activity in the open-field test. The results of this study provide first and direct evidence that carcinine, as a novel histamine H3 receptor antagonist, plays an important role in histaminergic neurons activation and might be useful in the treatment of certain diseases, such as epilepsy, and locomotor or cognitive deficit. British Journal of Pharmacology (2004) 143, 573,580. doi:10.1038/sj.bjp.0705978 [source]

Distinct pharmacology of rat and human histamine H3 receptors: role of two amino acids in the third transmembrane domain

BRITISH JOURNAL OF PHARMACOLOGY, Issue 7 2000
X Ligneau
Starting from the sequence of the human histamine H3 receptor (hH3R) cDNA, we have cloned the corresponding rat cDNA. Whereas the two deduced proteins show 93.5% overall homology and differ only by five amino acid residues at the level of the transmembrane domains (TMs), some ligands displayed distinct affinities. Thioperamide and ciproxifan were about 10 fold more potent at the rat than at the human receptor, whereas FUB 349 displayed a reverse preference. Histamine, (R),-methylhistamine, proxyfan or clobenpropit were nearly equipotent at H3 receptors of both species. The inverse discrimination patterns of ciproxifan and FUB 349 were partially changed by mutation of one amino acid (V122A), and fully abolished by mutation of two amino acids (A119T and V122A), in TM3 of the rH3R located in the vicinity of Asp114 purported to salt-link the ammonium group of histamine. Therefore, these two residues appear to be responsible for the distinct pharmacology of the H3R in the two species. British Journal of Pharmacology (2000) 131, 1247,1250; doi:10.1038/sj.bjp.0703712 [source]

Modulation of histamine H3 receptors in the brain of 6-hydroxydopamine-lesioned rats

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 11 2000
Oleg V. Anichtchik
Abstract Parkinson's disease is a major neurological disorder that primarily affects the nigral dopaminergic cells. Nigral histamine innervation is altered in human postmortem Parkinson's disease brains. However, it is not known if the altered innervation is a consequence of dopamine deficiency. The aim of the present study was to investigate possible changes in the H3 receptor system in a well-characterized model of Parkinson's disease , the 6-hydroxydopamine (6-OHDA) lesioned rats. Histamine immunohistochemistry showed a minor increase of the fibre density index but we did not find any robust increase of histaminergic innervation in the ipsilateral substantia nigra on the lesioned side. In situ hybridization showed equal histidine decarboxylase mRNA expression on both sides in the posterior hypothalamus. H3 receptors were labelled with N-alpha-[3H]-methyl histamine dihydrochloride ([3H] NAMH). Upregulation of binding to H3 receptors was found in the substantia nigra and ventral aspects of striatum on the ipsilateral side. An increase of GTP-,-[35S] binding after H3 agonist activation was found in the striatum and substantia nigra on the lesioned side. In situ hybridization of H3 receptor mRNA demonstrated region-specific mRNA expression and an increase of H3 receptor mRNA in ipsilateral striatum. Thus, the histaminergic system is involved in the pathological process after 6-OHDA lesion of the rat brain at least through H3 receptor. On the later stages of the neurotoxic damage, less H3 receptors became functionally active. Increased H3 receptor mRNA expression and binding may, for example, modulate GABAergic neuronal activity in dopamine-depleted striatum. [source]

Marked changes in signal transduction upon heteromerization of dopamine D1 and histamine H3 receptors

BRITISH JOURNAL OF PHARMACOLOGY, Issue 1 2009
Carla Ferrada
Background and purpose:, Functional interactions between the G protein-coupled dopamine D1 and histamine H3 receptors have been described in the brain. In the present study we investigated the existence of D1,H3 receptor heteromers and their biochemical characteristics. Experimental approach:, D1,H3 receptor heteromerization was studied in mammalian transfected cells with Bioluminescence Resonance Energy Transfer and binding assays. Furthermore, signalling through mitogen-activated protein kinase (MAPK) and adenylyl cyclase pathways was studied in co-transfected cells and compared with cells transfected with either D1 or H3 receptors. Key results:, Bioluminescence Resonance Energy Transfer and binding assays confirmed that D1 and H3 receptors can heteromerize. Activation of histamine H3 receptors did not lead to signalling towards the MAPK pathway unless dopamine D1 receptors were co-expressed. Also, dopamine D1 receptors, usually coupled to Gs proteins and leading to increases in cAMP, did not couple to Gs but to Gi in co-transfected cells. Furthermore, signalling via each receptor was blocked not only by a selective antagonist but also by an antagonist of the partner receptor. Conclusions and implications:, D1,H3 receptor heteromers constitute unique devices that can direct dopaminergic and histaminergic signalling towards the MAPK pathway in a Gs -independent and Gi -dependent manner. An antagonist of one of the receptor units in the D1,H3 receptor heteromer can induce conformational changes in the other receptor unit and block specific signals originating in the heteromer. This gives rise to unsuspected therapeutic potentials for G protein-coupled receptor antagonists. [source]

Histamine H3 -receptor agonists and imidazole-based H3 -receptor antagonists can be thermodynamically discriminated

BRITISH JOURNAL OF PHARMACOLOGY, Issue 4 2007
E A Harper
Background and purpose: Studies suggest that measurement of thermodynamic parameters can allow discrimination of agonists and antagonists. Here we investigate whether agonists and antagonists can be thermodynamically discriminated at histamine H3 receptors. Experimental approach: The pKL of the antagonist radioligand, [3H]-clobenpropit, in guinea-pig cortex membranes was estimated at 4, 12, 21 and 30°C in 20mM HEPES-NaOH buffer (buffer A), or buffer A containing 300mM CaCl2, (buffer ACa). pKI, values for ligands with varying intrinsic activity were determined in buffer A and ACa at 4, 12, 21 and 30°C. Key results: In buffer A, the pKL of [3H]-clobenpropit increased with decreasing temperature while it did not change in buffer ACa. The Bmax was not affected by temperature or buffer and nH values were not different from unity. In buffer A, pKI, values for agonists remained unchanged or decreased with decreasing temperature, while antagonist pKI values increased with decreasing temperature; agonist binding was entropy-driven while antagonist binding was enthalpy and entropy-driven. In buffer ACa, temperature had no effect on antagonist and agonist pKI values; both agonist and antagonist binding were enthalpy and entropy-driven. Conclusions and implications: The binding of H3 -receptor agonists and antagonists can be thermodynamically discriminated under conditions where agonist pKI, values are over-estimated (pKI,,pKapp). However, under conditions when agonist pKI ,pKapp, the thermodynamics underlying the binding of agonists are not different to those of antagonists. British Journal of Pharmacology (2007) 151, 504,517; doi:10.1038/sj.bjp.0707243 [source]