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H3 Receptors (h3 + receptor)

Distribution by Scientific Domains

Medical Sciences	56%
Life Sciences	26%
Chemistry	17%

Kinds of H3 Receptors

histamine h3 receptor

Terms modified by H3 Receptors

h3 receptor agonist

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]

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]

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]

Synthesis of 4,7,8a,9-tetrahydro-3H -diimidazo-[1,5- a:4,,5,- d]pyridine derivatives

JOURNAL OF HETEROCYCLIC CHEMISTRY, Issue 2 2002
Miguel F. Braña
The synthesis and evaluation of new ligands for the H3 receptor of histamine is described. These new compounds are diimidazopyridine derivatives readily prepared by a condensation reaction of spinacine and isocyanates. [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]

Subcutaneous histamine versus botulinum toxin type A in migraine prophylaxis: a randomized, double-blind study

EUROPEAN JOURNAL OF NEUROLOGY, Issue 1 2009
R. O. Millán-Guerrero
Objectives:, To compare the efficacy and tolerability of the subcutaneous administration of histamine and botulinum toxin type A (BoNTA) in migraine prophylaxis. Background:, Histamine has a selective affinity for H3 receptors and it may specifically inhibit the neurogenic edema response involved in migraine pathophysiology. Methods:, One hundred patients with migraine were selected in a 12-week double-blind controlled clinical trial to evaluate the efficacy of subcutaneous administration of histamine (1,10 ng twice a week) n = 50, compared with administration of 50 U of BoNTA (one injection cycle) n = 50. Results:, The data collected during the 4th week of treatment revealed a significant decrease in all parameters studied, in histamine and BoNTA (P < 0.001). After 4 weeks of treatment, but one injection cycle of 50 U BoNTA had only a 40-day period of efficacy. Conclusions:, This randomized study demonstrated that both histamine and BoNTA are similarly effective and well tolerated in reducing or eliminating headache in migraine prophylaxis. Low doses of histamine applied subcutaneously may represent a novel and effective therapeutic alternative in migraine patients and lay the clinical and pharmacological groundwork for the use of H3 agonist in migraine prophylaxis. [source]

Activation of histaminergic H3 receptors in the rat basolateral amygdala improves expression of fear memory and enhances acetylcholine release

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 3 2002
Iacopo Cangioli
Abstract The basolateral amygdala (BLA) is involved in learning that certain environmental cues predict threatening events. Several studies have shown that manipulation of neurotransmission within the BLA affects the expression of memory after fear conditioning. We previously demonstrated that blockade of histaminergic H3 receptors decreased spontaneous release of acetylcholine (ACh) from the BLA of freely moving rats, and impaired retention of fear memory. In the present study, we examined the effect of activating H3 receptors within the BLA on both ACh release and expression of fear memory. Using the microdialysis technique in freely moving rats, we found that the histaminergic H3 agonists R-,-methylhistamine (RAMH) and immepip, directly administered into the BLA, augmented spontaneous release of ACh in a similar manner. Levels of ACh returned to baseline on perfusion with control medium. Rats receiving intra-BLA, bilateral injections of the H3 agonists at doses similar to those enhancing ACh spontaneous release, immediately after contextual fear conditioning, showed stronger memory for the context,footshock association, as demonstrated by longer freezing assessed at retention testing performed 72 h later. Post-training, bilateral injections of 15 ng oxotremorine also had a similar effect on memory retention, supporting the involvement of the cholinergic system. Thus, our results further support a physiological role for synaptically released histamine, that in addition to affecting cholinergic transmission in the amygdala, modulates consolidation of fear memories [source]

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

Histamine induces neural stem cell proliferation and neuronal differentiation by activation of distinct histamine receptors

JOURNAL OF NEUROCHEMISTRY, Issue 2 2008
Anayansi Molina-Hernández
Abstract Histamine has neurotransmitter/neuromodulator functions in the adult brain, but its role during CNS development has been elusive. We studied histamine effects on proliferation, cell death and differentiation of neuroepithelial stem cells from rat cerebral cortex in vitro. RT-PCR and Western blot experiments showed that proliferating and differentiated cells express histamine H1, H2 and H3 receptors. Treatments with histamine concentrations (100 nM,1 mM) caused significant increases in cell numbers without affecting Nestin expression. Cell proliferation was evaluated by BrdU incorporation; histamine caused a significant increase dependent on H2 receptor activation. Apoptotic cell death during proliferation was significantly decreased at all histamine concentrations, and cell death was promoted in a concentration-dependent manner by histamine in differentiated cells. Immunocytochemistry studies showed that histamine increased 3-fold the number of neurons after differentiation, mainly by activation of H1 receptor, and also significantly decreased the glial (astrocytic) cell proportion, when compared to control conditions. In summary, histamine increases cell number during proliferative conditions, and has a neuronal-differentiating action on neural stem cells, suggesting that the elevated histamine concentration reported during development might play a role in cerebrocortical neurogenesis, by activation of H2 receptors to promote proliferation of neural precursors, and favoring neuronal fate by H1 -mediated stimulation. [source]

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

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]

Histamine H3 -receptor-mediated [35S]GTP,[S] binding: evidence for constitutive activity of the recombinant and native rat and human H3 receptors

BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2002
A Rouleau
Constitutive activity of the recombinant and native rat and human H3 receptors (H3Rs) was studied using H3R-mediated [35S]GTP,[S] binding and [3H]-arachidonic acid release. Ciproxifan, an inverse agonist at the rat H3R (rH3R), decreased [3H]arachidonic acid release from CHO cells expressing moderate densities (,200,300 fmol mg,1 protein) of the human H3R (hH3R). This effect occurred with the same magnitude than at the rH3R. The expression of the hH3R was associated with an increase in [35S]GTP,[S] binding to membranes of CHO cells. Ciproxifan decreased [35S]GTP,[S] binding to membranes of CHO (hH3R) cells. Both effects were correlated to receptor density and revealed that constitutive activity of the hH3R, although lower than that of the rH3R in this assay, was again observed at physiological densities (<500 fmol mg,1 protein). Ciproxifan was less potent at the human than the rat receptor, not only as an antagonist (Ki=45 nM), but also as an inverse agonist (EC50=15 nM). Constitutive activity of the hH3R was also evidenced using inhibition of [35S]GTP,[S] binding by unlabelled GTP,S. The expression of the hH3R generated a high affinity binding for GTP,S which was increased by imetit, but partially decreased by ciproxifan, therefore acting as a partial inverse agonist. [35S]GTP,[S] binding to rat brain membranes was decreased in several regions by thioperamide, ciproxifan and FUB 465, three inverse agonists at the H3R, whose effects were blocked by proxyfan, a neutral antagonist. [35S]GTP,[S] binding was also decreased by an A1 -adenosine receptor inverse agonist, but remained unchanged in the presence of inverse agonists at D2/D3 dopamine, H1 and H2 histamine, ,2 -adrenergic and , opioid receptors. In conclusion, the present study shows that the recombinant rat and human H3 receptors expressed at physiological densities display constitutive activity and suggests that constitutive activity of native H3Rs is one of the highest among G-protein-coupled receptors present in rat brain. British Journal of Pharmacology (2002) 135, 383,392; doi:10.1038/sj.bjp.0704490 [source]