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1.
Esbenshade TA Browman KE Bitner RS Strakhova M Cowart MD Brioni JD 《British journal of pharmacology》2008,154(6):1166-1181
The histamine H3 receptor, first described in 1983 as a histamine autoreceptor and later shown to also function as a heteroreceptor that regulates the release of other neurotransmitters, has been the focus of research by numerous laboratories as it represents an attractive drug target for a number of indications including cognition. The purpose of this review is to acquaint the reader with the current understanding of H3 receptor localization and function as a modulator of neurotransmitter release and its effects on cognitive processes, as well as to provide an update on selected H3 antagonists in various states of preclinical and clinical advancement. Blockade of centrally localized H3 receptors by selective H3 receptor antagonists has been shown to enhance the release of neurotransmitters such as histamine, ACh, dopamine and norepinephrine, among others, which play important roles in cognitive processes. The cognitive-enhancing effects of H3 antagonists across multiple cognitive domains in a wide number of preclinical cognition models also bolster confidence in this therapeutic approach for the treatment of attention deficit hyperactivity disorder, Alzheimer's disease and schizophrenia. However, although a number of clinical studies examining the efficacy of H3 receptor antagonists for a variety of cognitive disorders are currently underway, no clinical proof of concept for an H3 receptor antagonist has been reported to date. The discovery of effective H3 antagonists as therapeutic agents for the novel treatment of cognitive disorders will only be accomplished through continued research efforts that further our insights into the functions of the H3 receptor. 相似文献
2.
TR Miller I Milicic J Bauch J Du B Surber KE Browman K Marsh M Cowart JD Brioni TA Esbenshade 《British journal of pharmacology》2009,157(1):139-149
Background and purpose:
The histamine H3 receptor antagonist radioligand [3H]-A-349821 was characterized as a radiotracer for assessing in vivo receptor occupancy by H3 receptor antagonists that affect behaviour. This model was established as an alternative to ex vivo binding methods, for relating antagonist H3 receptor occupancy to blood levels and efficacy in preclinical models.Experimental approach:
In vivo cerebral cortical H3 receptor occupancy by [3H]-A-349821 was determined in rats from differences in [3H]-A-349821 levels in the isolated cortex and cerebellum, a brain region with low levels of H3 receptors. Comparisons were made to relate antagonist H3 receptor occupancy to blood levels and efficacy in a preclinical model of cognition, the five-trial inhibitory avoidance response in rat pups.Key results:
In adult rats, [3H]-A-349821, 1.5 µg·kg−1, penetrated into the brain and cleared more rapidly from cerebellum than cortex; optimally, [3H]-A-349821 levels were twofold higher in the latter. With increasing [3H]-A-349821 doses, cortical H3 receptor occupancy was saturable with a binding capacity consistent with in vitro binding in cortex membranes. In studies using tracer [3H]-A-349821 doses, ABT-239 and other H3 receptor antagonists inhibited H3 receptor occupancy by [3H]-A-349821 in a dose-dependent manner. Blood levels of the antagonists corresponding to H3 receptor occupancy were consistent with blood levels associated with efficacy in the five-trial inhibitory avoidance response.Conclusions and implications:
When employed as an occupancy radiotracer, [3H]-A-349821 provided valid measurements of in vivo H3 receptor occupancy, which may be helpful in guiding and interpreting clinical studies of H3 receptor antagonists. 相似文献3.
The cloning of the histamine H(3) receptor (H(3)R) cDNA in 1999 by Lovenberg et al. [10] allowed detailed studies of its molecular aspects and indicated that the H(3)R can activate several signal transduction pathways including G(i/o)-dependent inhibition of adenylyl cyclase, activation of phospholipase A(2), Akt and the mitogen activated kinase as well as the inhibition of the Na(+)/H(+) exchanger and inhibition of K(+)-induced Ca(2+) mobilization. Moreover, cloning of the H(3)R has led to the discovery several H(3)R isoforms generated through alternative splicing of the H(3)R mRNA. The H(3)R has gained the interest of many pharmaceutical companies as a potential drug target for the treatment of various important disorders like obesity, myocardial ischemia, migraine, inflammatory diseases and several CNS disorders like Alzheimer's disease, attention-deficit hyperactivity disorder and schizophrenia. In this paper, we review various molecular aspects of the hH(3)R including its signal transduction, dimerization and the occurrence of different H(3)R isoforms. 相似文献
4.
Medhurst AD Briggs MA Bruton G Calver AR Chessell I Crook B Davis JB Davis RP Foley AG Heslop T Hirst WD Medhurst SJ Ociepka S Ray A Regan CM Sargent B Schogger J Stean TO Trail BK Upton N White T Orlek B Wilson DM 《Biochemical pharmacology》2007,73(8):1182-1194
GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1H-1,4-diazepine) are novel and selective non-imidazole histamine H(3) receptor antagonists from distinct chemical series with high affinity for human (pK(i)=9.67+/-0.06 and 9.49+/-0.09, respectively) and rat (pK(i)=9.08+/-0.16 and 9.12+/-0.14, respectively) H(3) receptors expressed in cerebral cortex. At the human recombinant H(3) receptor, GSK207040 and GSK334429 were potent functional antagonists (pA(2)=9.26+/-0.04 and 8.84+/-0.04, respectively versus H(3) agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC(50)=9.20+/-0.36 and 8.59+/-0.04 versus basal GTPgammaS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [(3)H]-R-alpha-methylhistamine binding (ED(50)=0.03 and 0.35 mg/kg, respectively). Functional antagonism of central H(3) receptors was demonstrated by blockade of R-alpha-methylhistamine-induced dipsogenia in rats (ID(50)=0.02 and 0.11 mg/kg p.o. for GSK207040 and GSK334429, respectively). In more pathophysiologically relevant pharmacodynamic models, GSK207040 (0.1, 0.3, 1 and 3mg/kg p.o.) and GSK334429 (0.3, 1 and 3mg/kg p.o.) significantly reversed amnesia induced by the cholinergic antagonist scopolamine in a passive avoidance paradigm. In addition, GSK207040 (0.1, 0.3 and 1mg/kg p.o.) and GSK334429 (3 and 10mg/kg p.o.) significantly reversed capsaicin-induced reductions in paw withdrawal threshold, suggesting for the first time that blockade of H(3) receptors may be able to reduce tactile allodynia. Novel H(3) receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain. 相似文献
5.
Since its discovery at the beginning of the 20th century, histamine has been established to play a pathophysiological regulatory role in cellular events through binding to four types of G-protein-coupled histamine receptors that are differentially expressed in various cell types. The discovery, at the turn of the millennium, that the histamine H4 receptor is largely expressed in haemopoietic cells as well as its chemotactic properties designate its regulatory role in the immune system. H4 receptors modulate eosinophil migration and selective recruitment of mast cells leading to amplification of histamine-mediated immune responses and eventually to chronic inflammation. H4 receptor involvement in dendritic cell activation and T cell differentiation documents its immunomodulatory function. The characterization of the H4 as the immune system histamine receptor directed growing attention towards its therapeutic exploitation in inflammatory disorders, such as allergy, asthma, chronic pruritus and autoimmune diseases. The efficacy of a number of H4 receptor ligands has been evaluated in in vivo and in vitro animal models of disease and in human biological samples. However, before reaching decisive conclusions on H4 receptor pathophysiological functions and therapeutic exploitation, identification of genetic polymorphisms and interspecies differences in its relative actions and pharmacological profile need to be addressed and taken into consideration. Despite certain variations in the reported findings, the available data strongly point to the H4 receptor as a novel target for the pharmacological modulation of histamine-transferred immune signals and offer an optimistic perspective for the therapeutic exploitation of this promising new drug target in inflammatory disorders. 相似文献
6.
T Nakamura T Yoshikawa N Noguchi A Sugawara A Kasajima H Sasano K Yanai 《British journal of pharmacology》2014,171(1):171-185
BACKGROUND AND PURPOSE
Histamine and its receptors in the CNS play important roles in energy homeostasis. Here, we have investigated the expression and role of histamine receptors in pancreatic beta cells, which secrete insulin.EXPERIMENTAL APPROACH
The expression of histamine receptors in pancreatic beta cells was examined by RT-PCR, Western blotting and immunostaining. Insulin secretion assay, ATP measurement and calcium imaging studies were performed to determine the function and signalling pathway of histamine H3 receptors in glucose-induced insulin secretion (GIIS) from MIN6 cells, a mouse pancreatic beta cell line. The function and signalling pathway of H3 receptors in MIN6 cell proliferation were examined using pharmacological assay and Western blotting.KEY RESULTS
Histamine H3 receptors were expressed in pancreatic beta cells. A selective H3 receptor agonist, imetit, and a selective inverse H3 receptor agonist, JNJ-5207852, had inhibitory and facilitatory effects, respectively, on GIIS in MIN6 cells. Neither imetit nor JNJ-5207852 altered intracellular ATP concentration, or intracellular calcium concentration stimulated by glucose and KCl, indicating that GIIS signalling was affected by H3 receptor signalling downstream of the increase in intracellular calcium concentration. Moreover, imetit attenuated bromodeoxyuridine incorporation in MIN6 cells. The phosphorylation of cAMP response element-binding protein (CREB), which facilitated beta cell proliferation, was inhibited, though not significantly, by imetit, indicating that activated H3 receptors inhibited MIN6 cell proliferation, possibly by decreasing CREB phosphorylation.CONCLUSIONS AND IMPLICATIONS
Histamine H3 receptors were expressed in mouse beta cells and could play a role in insulin secretion and, possibly, beta cell proliferation. 相似文献7.
Ahmed A Othman George Haig Hana Florian Charles Locke Lev Gertsik Sandeep Dutta 《British journal of clinical pharmacology》2014,77(6):965-974
Aims
ABT-288 is a potent and selective H3 receptor antagonist with procognitive effects in several preclinical models. In previous studies, 3 mg once daily was the maximal tolerated dose in healthy volunteers. This study characterized the safety, tolerability and pharmacokinetics of ABT-288 in stable subjects with schizophrenia.Methods
This was a randomized, double-blind, placebo-controlled, dose-escalating study of ABT-288 (10 dose levels, from 1 to 60 mg once daily for 14 days) in stable subjects with schizophrenia treated with an atypical antipsychotic. In each dose group, five to seven and two to three participants were assigned to ABT-288 and placebo, respectively.Results
Of the 67 participants enrolled, nine participants (on ABT-288) were prematurely discontinued, in seven of these due to adverse events. ABT-288 was generally safe and tolerated at doses up to 45 mg once daily. The most common adverse events, in decreasing frequency (from 31 to 5%), were abnormal dreams, headache, insomnia, dizziness, somnolence, dysgeusia, dry mouth, psychotic disorder, parosmia and tachycardia. Adverse events causing early termination were psychotic events (four) and increased creatine phosphokinase, pyrexia and insomnia (one each). The half-life of ABT-288 ranged from 28 to 51 h, and steady state was achieved by day 12 of dosing. At comparable multiple doses, ABT-288 exposure in subjects with schizophrenia was 45% lower than that previously observed in healthy subjects. At trough, ABT-288 cerebrospinal fluid concentrations were 40% of the total plasma concentrations.Conclusions
ABT-288 was tolerated at a 15-fold higher dose and 12-fold higher exposures in subjects with schizophrenia than previously observed in healthy volunteers. The greater ABT-288 tolerability was not due to limited brain uptake. 相似文献8.
Slack RJ Russell LJ Hall DA Luttmann MA Ford AJ Saunders KA Hodgson ST Connor HE Browning C Clark KL 《British journal of pharmacology》2011,164(6):1627-1641
BACKGROUND AND PURPOSE
Preclinical pharmacological characterization of GSK1004723, a novel, dual histamine H1 and H3 receptor antagonist.EXPERIMENTAL APPROACH
GSK1004723 was characterized in vitro and in vivo using methods that included radioligand binding, intracellular calcium mobilization, cAMP production, GTPγS binding, superfused human bronchus and guinea pig whole body plethysmography.KEY RESULTS
In cell membranes over-expressing human recombinant H1 and H3 receptors, GSK1004723 displayed high affinity, competitive binding (H1 pKi = 10.2; H3 pKi = 10.6). In addition, GSK1004723 demonstrated slow dissociation from both receptors with a t1/2 of 1.2 and 1.5 h for H1 and H3 respectively. GSK1004723 specifically antagonized H1 receptor mediated increases in intracellular calcium and H3 receptor mediated increases in GTPγS binding. The antagonism exerted was retained after cell washing, consistent with slow dissociation from H1 and H3 receptors. Duration of action was further evaluated using superfused human bronchus preparations. GSK1004723 (100 nmol·L−1) reversed an established contractile response to histamine. When GSK1004723 was removed from the perfusate, only 20% recovery of the histamine response was observed over 10 h. Moreover, 21 h post-exposure to GSK1004723 there remained almost complete antagonism of responses to histamine. In vivo pharmacology was studied in conscious guinea pigs in which nasal congestion induced by intranasal histamine was measured indirectly (plethysmography). GSK1004723 (0.1 and 1 mg·mL−1 intranasal) antagonized the histamine-induced response with a duration of up to 72 h.CONCLUSIONS AND IMPLICATIONS
GSK1004723 is a potent and selective histamine H1 and H3 receptor antagonist with a long duration of action and represents a potential novel therapy for allergic rhinitis. 相似文献9.
M Gschwandtner B Koether T Werfel H Stark R Gutzmer 《British journal of pharmacology》2013,170(1):136-143
Background and Purpose
Since the identification of the histamine H4 receptor, several ligands activating this receptor have been described and more compounds are in development. These ligands are well characterized in pharmacological assays, including radioligand competition binding studies, GTPγS and GTPase assays. In most cases, these experiments are performed in transfected cell lines, expressing unnaturally high levels of target receptors and G-protein signalling components. In this study we investigated the specific properties of H4 receptor ligands in native cells.Experimental Approach
Histamine and five different H4 receptor agonists – 4-methylhistamine, UR-PI376, clobenpropit, VUF8430 and ST-1006 – were characterized in freshly isolated human monocytes. The ligands (10 nM–10 μM) were tested as inhibitors of IL-12p70 secretion from human monocytes and the effects of the H2 receptor antagonist ranitidine and the H4 receptor antagonist JNJ7777120 on their action was investigated.Key Results
Histamine and all the tested agonists reduced IL-12p70 secretion into monocyte supernatants by 40–70%. The potencies varied with pEC50 values ranging from 5.7 to 6.9, depending on the agonist used. All potencies were lower than those determined in the original investigations of the compounds. Pretreatment of monocytes with H2 or H4 receptor antagonists showed that some H4 receptor ligands also had low activity at the H2 receptor.Conclusions and Implications
Our study demonstrates discrepancies between the potencies obtained from assays in transfected cell lines and assays in native human cells, indicating the importance of evaluating H4 receptor ligands in native cells.Linked Articles
This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 相似文献10.
I V Tabarean 《British journal of pharmacology》2013,170(2):415-425
BACKGROUND AND PURPOSE
Histamine H1 receptors are highly expressed in hypothalamic neurons and mediate histaminergic modulation of several brain-controlled physiological functions, such as sleep, feeding and thermoregulation. In spite of the fact that the mouse is used as an experimental model for studying histaminergic signalling, the pharmacological characteristics of mouse H1 receptors have not been studied. In particular, selective and potent H1 receptor agonists have not been identified.EXPERIMENTAL APPROACH
Ca2+ imaging using fura-2 fluorescence signals and whole-cell patch-clamp recordings were carried out in mouse preoptic/anterior hypothalamic neurons in culture.KEY RESULTS
The H1 receptor antagonists mepyramine and trans-triprolidine potently antagonized the activation by histamine of these receptors with IC50 values of 0.02 and 0.2 μM respectively. All H1 receptor agonists studied had relatively low potency at the H1 receptors expressed by these neurons. Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine had full-agonist activity with potencies similar to that of histamine. In contrast, 2-pyridylethylamine and betahistine showed only partial agonist activity and lower potency than histamine. The histamine receptor agonist, 6-[2-(4-imidazolyl)ethylamino]-N-(4-trifluoromethylphenyl)heptanecarboxamide (HTMT) had no agonist activity at the H1 receptors H1 receptors expressed by mouse preoptic/anterior hypothalamic neurons but displayed antagonist activity.CONCLUSIONS AND IMPLICATIONS
Methylhistaprodifen and 2-(3-trifluoromethylphenyl)histamine were identified as full agonists of mouse H1 receptors. These results also indicated that histamine H1 receptors in mice exhibited a pharmacological profile in terms of agonism, significantly different from those of H1 receptors expressed in other species. 相似文献11.
Yao BB Witte DG Miller TR Carr TL Kang CH Cassar S Faghih R Bennani YL Surber BW Hancock AA Esbenshade TA 《Neuropharmacology》2006,50(4):468-478
Selective radioligands for histamine H(3) receptors have been used to characterize H(3) receptor pharmacology by radioligand binding assays and to determine H(3) receptor distribution by tissue autoradiography. Here we report the synthesis and receptor binding characterization of [(3)H]A-317920 (furan-2-carboxylic acid(2-[4-[3-([3,5-(3)H]4-cyclopropanecarbonyl-phenoxy)-propyl]-piperazin-1-yl]-1-methyl-2-oxo-ethyl)-amide), a high affinity inverse agonist radioligand for the rat H(3) receptor. The binding of [(3)H]A-317920 to rat cortical and cloned H(3) receptors revealed fast on- and slower off-rate kinetics with calculated K(d) values in agreement with those determined in saturation binding assays (0.2 nM for both receptors). Further, we compared [(3)H]A-317920 with the agonist [(3)H](N)-alpha-methylhistamine ([(3)H]NalphaMH) as radioligand tools to study receptor pharmacology. Agonists and antagonists displaced [(3)H]NalphaMH with one-site binding characteristics and Hill slopes approached unity. In contrast, although antagonists exhibited one-site binding, [(3)H]A-317920 displacement by agonists was best fit by two-site binding models, and the potencies of the high affinity, GDP-sensitive sites correlated with the potencies defined in [(3)H]NalphaMH binding. Unlike [(125)I]iodoproxyfan, [(3)H]A-317920 exhibits potent and selective binding to rat H(3) receptors with low binding to non-H(3) sites, including cytochrome P450. These findings show that [(3)H]A-317920 is a potent rat H(3) receptor antagonist radioligand and has utility for studying H(3) receptor pharmacology. 相似文献
12.
The central histaminergic actions are mediated by H1, H2, H3 and H4 receptors. The histamine H3 receptor regulates the release of histamine and a number of other neurotransmitters and thereby plays a role in cognitive and homeostatic processes. Elevated histamine levels suppress seizure activities and appear to confer neuroprotection. The H3 receptors have a number of enigmatic features like constitutive activity, interspecies variation, distinct ligand binding affinities and differential distribution of prototypic splice variants in the CNS. Furthermore, this Gi/Go-protein-coupled receptor modulates several intracellular signalling pathways whose involvement in epilepsy and neurotoxicity are yet to be ascertained and hence represent an attractive target in the search for new anti-epileptogenic drugs. So far, H3 receptor antagonists/inverse agonists have garnered a great deal of interest in view of their promising therapeutic properties in various CNS disorders including epilepsy and related neurotoxicity. However, a number of experiments have yielded opposing effects. This article reviews recent works that have provided evidence for diverse mechanisms of antiepileptic and neuroprotective effects that were observed in various experimental models both in vitro and in vivo. The likely reasons for the apparent disparities arising from the literature are also discussed with the aim of establishing a more reliable basis for the future use of H3 receptor antagonists, thus improving their utility in epilepsy and associated neurotoxicity. 相似文献
13.
Background and Purpose
Schizophrenia is a highly debilitating disorder characterized by hallucinations and delusions, but also impaired cognition such as memory. While hallucinations and delusions are the main target for pharmacological treatment, cognitive impairments are rarely treated. Evidence exists that histamine has a role in the cognitive deficits in schizophrenia, which could be the basis of the development of a histamine-type treatment. Histamine H3 antagonists have been shown to improve memory performance in experimental animals, but these effects have been little investigated in humans within the context of impaired cognition in schizophrenia and using sensitive measures of brain activity. In the present study, the effects of betahistine (H3 antagonist/H1 agonist) on learning and memory, and associated brain activity were assessed.Experimental Approach
Sixteen healthy volunteers (eight female) aged between 18 and 50 years received two p.o. doses of betahistine (48 mg) or placebo separated by 30 min, on separate days according to a two-way, double-blind, crossover design. Volunteers performed an N-back working memory task and a spatial paired associates learning task while being scanned using a MRI scanner.Key Results
Task-related activity changes in well-defined networks and performance were observed. No betahistine-induced changes in brain activity were found in these networks. Alternatively, liberal whole-brain analyses showed activity changes in areas outside task networks, like the lateral geniculate nucleus.Conclusions and Implications
Clear effects of betahistine on working memory could not be established. Future studies should use higher doses and explore the role of histamine in visual information processing.Linked Articles
This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 相似文献14.
S Ashworth A Berges E A Rabiner A A Wilson R A Comley R Y K Lai R Boardley G Searle R N Gunn M Laruelle V J Cunningham 《British journal of pharmacology》2014,171(5):1241-1249
BACKGROUND AND PURPOSE
This study aimed to investigate the relationship between the plasma concentration (PK) of the novel histamine H3 receptor antagonist, GSK239512, and the brain occupancy of H3 receptors (RO) in healthy human volunteers.EXPERIMENTAL APPROACH
PET scans were obtained after i.v. administration of the H3-specific radioligand [11C]GSK189254. Each subject was scanned before and after single oral doses of GSK239512, at 4 and 24 h after dose. PET data were analysed by compartmental analysis, and regional RO estimates were obtained by graphical analysis of changes in the total volumes of distribution of the radioligand, followed by a correction for occupancy by the high affinity radioligand. The PK/RO relationship was analysed by a population-modelling approach, using the average PK of GSK239512 during each scan.KEY RESULTS
Following administration of GSK239512, there was a reduction in the brain uptake of [11C]GSK189254 in all regions, including cerebellum. RO at 4 h was higher than at 24 h, and the PK/RO model estimated a PK associated with 50% of RO of 0.0068 ng·mL−1. This corresponds to a free concentration of 4.50 × 10−12 M (pK = 11.3).CONCLUSIONS AND IMPLICATIONS
The affinity of GSK239512 for brain H3 receptors in humans in vivo is much higher than that expected from studies in vitro, and higher than that observed in PET studies in pigs. The study illustrates the utility of carrying out PET studies in humans early in drug development, providing accurate quantification of GSK239512 RO in vivo as a function of time and dose. 相似文献15.
S Nijmeijer H Engelhardt S Schultes A C van de Stolpe V Lusink C de Graaf M Wijtmans E E J Haaksma I J P de Esch K Stachurski H F Vischer R Leurs 《British journal of pharmacology》2013,170(1):89-100
Background and Purpose
The recently proposed binding mode of 2-aminopyrimidines to the human (h) histamine H4 receptor suggests that the 2-amino group of these ligands interacts with glutamic acid residue E1825.46 in the transmembrane (TM) helix 5 of this receptor. Interestingly, substituents at the 2-position of this pyrimidine are also in close proximity to the cysteine residue C983.36 in TM3. We hypothesized that an ethenyl group at this position will form a covalent bond with C983.36 by functioning as a Michael acceptor. A covalent pyrimidine analogue will not only prove this proposed binding mode, but will also provide a valuable tool for H4 receptor research.Experimental Approach
We designed and synthesized VUF14480, and pharmacologically characterized this compound in hH4 receptor radioligand binding, G protein activation and β-arrestin2 recruitment experiments. The ability of VUF14480 to act as a covalent binder was assessed both chemically and pharmacologically.Key Results
VUF14480 was shown to be a partial agonist of hH4 receptor-mediated G protein signalling and β-arrestin2 recruitment. VUF14480 bound covalently to the hH4 receptor with submicromolar affinity. Serine substitution of C983.36 prevented this covalent interaction.Conclusion and Implications
VUF14480 is thought to bind covalently to the hH4 receptor-C983.36 residue and partially induce hH4 receptor-mediated G protein activation and β-arrestin2 recruitment. Moreover, these observations confirm our previously proposed binding mode of 2-aminopyrimidines. VUF14480 will be a useful tool to stabilize the receptor into an active confirmation and further investigate the structure of the active hH4 receptor.Linked Articles
This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 相似文献16.
WM Connelly FC Shenton N Lethbridge R Leurs HJ Waldvogel RLM Faull G Lees PL Chazot 《British journal of pharmacology》2009,157(1):55-63
Background and purpose:
The histamine H4 receptor is the most recently identified of the G protein-coupled histamine receptor family and binds several neuroactive drugs, including amitriptyline and clozapine. So far, H4 receptors have been found only on haematopoietic cells, highlighting its importance in inflammatory conditions. Here we investigated the possibility that H4 receptors may be expressed in both the human and mouse CNS.Methods:
Immunological and pharmacological studies were performed using a novel anti-H4 receptor antibody in both human and mouse brains, and electrophysiological techniques in the mouse brain respectively. Pharmacological tools, selective for the H4 receptor and patch clamp electrophysiology, were utilized to confirm functional properties of the H4 receptor in layer IV of the mouse somatosensory cortex.Results:
Histamine H4 receptors were prominently expressed in distinct deep laminae, particularly layer VI, in the human cortex, and mouse thalamus, hippocampal CA4 stratum lucidum and layer IV of the cerebral cortex. In layer IV of the mouse somatosensory cortex, the H4 receptor agonist 4-methyl histamine (20 µmol·L−1) directly hyperpolarized neurons, an effect that was blocked by the selective H4 receptor antagonist JNJ 10191584, and promoted outwardly rectifying currents in these cells. Monosynaptic thalamocortical CNQX-sensitive excitatory postsynaptic potentials were not altered by 4-methyl histamine (20 µmol·L−1) suggesting that H4 receptors did not act as hetero-receptors on thalamocortical glutamatergic terminals.Conclusions and implications:
This is the first demonstration that histamine H4 receptors are functionally expressed on neurons, which has major implications for the therapeutic potential of these receptors in neurology and psychiatry. 相似文献17.
Cecilia Flores-Clemente Angélica Osorio-Espinoza Juan Escamilla-Sánchez Rob Leurs Juan-Manuel Arias José-Antonio Arias-Monta?o 《British journal of pharmacology》2013,170(1):127-135
Background and Purpose
An alanine to valine exchange at amino acid position 280 (A280V) in the third intracellular loop of the human histamine H3 receptor was first identified in a patient suffering from Shy–Drager syndrome and later reported as a risk factor for migraine. Here, we have compared the pharmacological and signalling properties of wild-type (hH3RWT) and A280V mutant (hH3RA280V) receptors stably expressed in CHO-K1 cells.Experimental Approach
The hH3RA280V cDNA was created by overlapping extension PCR amplification. Receptor expression and affinity were assessed by radioligand (N-α-[methyl-3H]-histamine) binding to cell membranes, and receptor function by the inhibition of forskolin-induced cAMP accumulation and stimulation of ERK1/2 phosphorylation in intact cells, as well as stimulation of [35S]-GTPγS binding to cell membranes.Key Results
Both receptors were expressed at similar levels with no significant differences in their affinities for H3 receptor ligands. Upon activation the hH3RWT was significantly more efficacious to inhibit forskolin-induced cAMP accumulation and to stimulate [35S]-GTPγS binding, with no difference in pEC50 estimates. The hH3RWT was also more efficacious to stimulate ERK1/2 phosphorylation, but this difference was not significant. The inverse agonist ciproxifan was more efficacious at hH3RWT to reduce [35S]-GTPγS binding but, for both receptors, failed to enhance forskolin-induced cAMP accumulation.Conclusions and Implications
The A280V mutation reduces the signalling efficacy of the human H3 receptor. This effect may be relevant to the pathophysiology of disorders associated with the mutation.Linked Articles
This article is part of a themed issue on Histamine Pharmacology Update. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2013.170.issue-1 相似文献18.
Carla Ferrada Estefanía Moreno Vicent Casadó Gerold Bongers Antoni Cortés Josefa Mallol Enric I Canela Rob Leurs Sergi Ferré Carme Lluís Rafael Franco 《British journal of pharmacology》2009,157(1):64-75
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. 相似文献19.
Herman D Lim Maristella Adami Elena Guaita Thomas Werfel Rogier A Smits Iwan JP de Esch Remko A Bakker Ralf Gutzmer Gabriella Coruzzi Rob Leurs 《British journal of pharmacology》2009,157(1):34-43
Background and purpose:
We compare the pharmacological profiles of a new histamine H4 receptor agonist 2-(2-guanidinoethyl)isothiourea (VUF 8430) with that of a previously described H4 receptor agonist, 4-methylhistamine.Experimental approach:
Radioligand binding and functional assays were performed using histamine H4 receptors expressed in mammalian cell lines. Compounds were also evaluated ex vivo in monocyte-derived dendritic cells endogenously expressing H4 receptors and in vivo in anaesthetized rats for gastric acid secretion activity.Key results:
Both VUF 8430 and 4-methylhistamine were full agonists at human H4 receptors with lower affinity at rat and mouse H4 receptors. Both compounds induced chemotaxis of monocyte-derived dendritic cells. VUF 8430 also showed reasonable affinity and was a full agonist at the H3 receptor. Agmatine is a metabolite of arginine, structurally related to VUF 8430, and was a H4 receptor agonist with micromolar affinity. At histamine H3 receptors, agmatine was a full agonist, whereas 4-methylhistamine was an agonist only at high concentrations. Both VUF 8430 and agmatine were inactive at H1 and H2 receptors, whereas 4-methylhistamine is as active as histamine at H2 receptors. In vivo, VUF 8430 only caused a weak secretion of gastric acid mediated by H2 receptors, whereas 4-methylhistamine, dimaprit, histamine and amthamine, at equimolar doses, induced 2.5- to 6-fold higher output than VUF 8430.Conclusions and implications:
Our results suggest complementary use of 4-methylhistamine and VUF 8430 as H4 receptor agonists. Along with H4 receptor antagonists, both agonists can serve as useful pharmacological tools in studies of histamine H4 receptors. 相似文献20.
Diego J Martinel Lamas Maximo Croci Eliana Carabajal Ernesto J V Crescenti Lorena Sambuco Noelia A Massari Rosa M Bergoc Elena S Rivera Vanina A Medina 《British journal of pharmacology》2013,170(1):188-199