Activation of histamine H3 receptors in human nasal mucosa inhibits sympathetic vasoconstriction

The peripheral histamine H3 receptor is a presynaptic heterologous receptor located on postganglionic sympathetic nerve fibers innervating sympathetic effector systems such as blood vessels and the heart. An extensive body of evidence shows that activation of the histamine H3 receptor attenuates sympathetic tone by presynaptic inhibition of noradrenaline release. It is proposed that this sympathoinhibitory action, in vivo, leads to reduced vasoconstriction, thereby eliciting a vasodilatory effect. In humans, the peripheral histamine H3 receptor has also been shown to exert a sympathoinhibitory function on specific peripheral autonomic effector systems. For example, human saphenous vein and heart possess functional presynaptic histamine H3 receptors on the sympathetic nerve terminals that upon activation decrease the sympathetic tone to these respective organs. The present studies were conducted to define the role of histamine H3 receptors on neurogenic sympathetic vasoconstrictor responses in human nasal turbinate mucosa. Contractility studies were conducted to evaluate the effect of histamine H3 receptor activation on sympathetic vasoconstriction in surgically isolated human nasal turbinate mucosa. We found that the histamine H3 receptor agonist, (R)-alpha-methylhistamine (30 and 300 nM), inhibited electrical field stimulation-induced (neurogenic) sympathetic vasoconstriction in a concentration-dependent fashion. Pretreatment with the selective histamine H3 receptor antagonist, clobenpropit (100 nM), blocked the sympathoinhibitory effect of (R)-alpha-methylhistamine on the neurogenic sympathetic vasoconstriction. In addition, analysis of Taqman mRNA expression studies showed a specific, high level of distribution of the histamine H3 receptor localized in the human nasal mucosa.Taken together, these studies indicate that histamine H3 receptors modulate vascular contractile responses in human nasal mucosa most likely by inhibiting noradrenaline release from sympathetic nerve terminals in nasal mucosa. It is further suggested that histamine H3 receptors may play a role in the regulation of vascular tone and nasal patency in histamine-dependent allergic nasal congestive disease.     

Histamine H3 receptor activation inhibits glutamate release from rat striatal synaptosomes

The release of glutamate from striatal synaptosomes induced by depolarisation with 4-aminopyridine (4-AP) was studied by a method based on the fluorescent properties of the NAPDH formed by the metabolism of the neurotransmitter by glutamate dehydrogenase.Ca²⁺-dependent, depolarisation-induced glutamate release was inhibited in a concentration-dependent manner by the selective histamine H₃ agonist immepip. Best-fit estimates were: maximum inhibition 60±10% and IC₅₀ 68±10 nM. The effect of 300 nM immepip on depolarisation-evoked glutamate release was reversed by the selective H₃ antagonist thioperamide in a concentration-dependent manner (EC₅₀ 23 nM, K_i 4 nM).In fura-2-loaded synaptosomes, the increase in the intracellular concentration of Ca²⁺ ([Ca²⁺]_i) evoked by 4-AP-induced depolarisation (resting level 167±14 nM; Δ[Ca²⁺]_i 88±15 nM) was modestly, but significantly reduced (29±5% inhibition) by 300 nM immepip. The action of the H₃ agonist on depolarisation-induced changes in [Ca²⁺]_i was reversed by 100 nM thioperamide.Taken together, our results indicate that histamine modulates the release of glutamate from corticostriatal nerve terminals. Inhibition of depolarisation-induced Ca²⁺ entry through voltage-dependent Ca²⁺ channels appears to account for the effect of H₃ receptor activation on neurotransmitter release. Modulation of glutamatergic transmission in rat striatum may have important consequences for the function of basal ganglia and therefore for the control of motor behaviour.     

Histamine H3 receptor activation inhibits glutamate release from rat striatal synaptosomes.

The release of glutamate from striatal synaptosomes induced by depolarisation with 4-aminopyridine (4-AP) was studied by a method based on the fluorescent properties of the NAPDH formed by the metabolism of the neurotransmitter by glutamate dehydrogenase.

Ca²⁺-dependent, depolarisation-induced glutamate release was inhibited in a concentration-dependent manner by the selective histamine H₃ agonist immepip. Best-fit estimates were: maximum inhibition 60±10% and IC₅₀ 68±10 nM. The effect of 300 nM immepip on depolarisation-evoked glutamate release was reversed by the selective H₃ antagonist thioperamide in a concentration-dependent manner (EC₅₀ 23 nM, K_i 4 nM).

In fura-2-loaded synaptosomes, the increase in the intracellular concentration of Ca²⁺ ([Ca²⁺]_i) evoked by 4-AP-induced depolarisation (resting level 167±14 nM; Δ[Ca²⁺]_i 88±15 nM) was modestly, but significantly reduced (29±5% inhibition) by 300 nM immepip. The action of the H₃ agonist on depolarisation-induced changes in [Ca²⁺]_i was reversed by 100 nM thioperamide.

Taken together, our results indicate that histamine modulates the release of glutamate from corticostriatal nerve terminals. Inhibition of depolarisation-induced Ca²⁺ entry through voltage-dependent Ca²⁺ channels appears to account for the effect of H₃ receptor activation on neurotransmitter release. Modulation of glutamatergic transmission in rat striatum may have important consequences for the function of basal ganglia and therefore for the control of motor behaviour.     

Unique roles of G protein-coupled histamine H2 and gastrin receptors in growth and differentiation of gastric mucosa

Disruption of histamine H2 receptor and gastrin receptor had different effects growth of gastric mucosa: hypertrophy and atrophy, respectively. To clarify the roles of gastrin and histamine H2 receptors in gastric mucosa, mice deficient in both (double-null mice) were generated and analyzed. Double-null mice exhibited atrophy of gastric mucosae, marked hypergastrinemia and higher gastric pH than gastrin receptor-null mice, which were unresponsive even to carbachol. Comparison of gastric mucosae from 10-week-old wild-type, histamine H2 receptor-null, gastrin receptor-null and double-null mice revealed unique roles of these receptors in gastric mucosal homeostasis. While small parietal cells and increases in the number and mucin contents of mucous neck cells were secondary to impaired acid production, the histamine H2 receptor was responsible for chief cell maturation in terms of pepsinogen expression and type III mucin. In double-null and gastrin receptor-null mice, despite gastric mucosal atrophy, surface mucous cells were significantly increased, in contrast to gastrin-null mice. Thus, it is conceivable that gastrin-gene product(s) other than gastrin-17, in the stimulated state, may exert proliferative actions on surface mucous cells independently of the histamine H2 receptor. These findings provide evidence that different G-protein coupled-receptors affect differentiation into different cell lineages derived from common stem cells in gastric mucosa.     

Structural and functional characterization of gastric mucosa and central nervous system in histamine H2 receptor-null mice

To examine the physiological role of the histamine H(2) receptor, histamine H(2) receptor-null mice were generated by homologous recombination. Histamine H(2) receptor-null mice, which developed normally and were fertile and healthy into adulthood, exhibited markedly enlarged stomachs and marked hypergastrinemia. The former was due to hyperplasia of gastric gland cells (small-sized parietal cells, enterochromaffin-like cells and mucous neck cells which were rich in mucin), but not of gastric surface mucous cells, which were not increased in number as compared with those in wild-type mice despite the marked hypergastrinemia. Basal gastric pH was slightly but significantly higher in histamine H(2) receptor-null mice. Although carbachol but not gastrin induced in vivo gastric acid production in histamine H(2) receptor-null mice, gastric pH was elevated by both muscarinic M(3) and gastrin antagonists. Thus, both gastrin and muscarinic receptors appear to be directly involved in maintaining gastric pH in histamine H(2) receptor-null mice. Interestingly, gastric glands from wild-type mice treated with an extremely high dose of subcutaneous lansoprazole (10 mg/kg body weight) for 3 months were very similar to those from histamine H(2) receptor-null mice. Except for hyperplasia of gastric surface mucous cells, the findings for gastric glands from lansoprazole-treated wild-type mice were almost identical to those from gastric glands from histamine H(2) receptor-null mice. Therefore, it is possible that the abnormal gastric glands in histamine H(2) receptor-null mice are secondary to the severe impairment of gastric acid production, induced by the histamine H(2) receptor disruption causing marked hypergastrinemia. Analyses of the central nervous system (CNS) of histamine H(2) receptor-null mice revealed these mice to be different from wild-type mice in terms of spontaneous locomotor activity and higher thresholds for electrically induced convulsions. Taken together, these results suggest that (1) gastrin receptors are functional in parietal cells in histamine H(2) receptor-null mice, (2) abnormal gastric glands in histamine H(2) receptor-null mice may be secondary to severe impairment of gastric acid production and secretion and (3) histamine H(2) receptors are functional in the central nervous system.     

Histamine H3 receptor antagonists in relation to epilepsy and neurodegeneration: a systemic consideration of recent progress and perspectives

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.     

Histamine H3 receptor-mediated inhibition of gastric acid secretion in conscious dogs

Summary The effect of (R)-methylhistamine (MH) and thioperamide (selective agonist and antagonist respectively of histamine H₃ receptors) was examined in conscious gastric fistula dogs to investigate the role of histamine H₃ receptors in the control of basal and stimulated gastric acid secretion. Intravenous infusion of MH at 0.3 and 0.6 mol/kg/h caused a significant reduction of the 2-deoxy-d-glucose (2-DG)-stimulated acid output, maximal inhibition being 60%. The inhibitory effect of MH was counteracted by thioperamide (0.1 mol/kg/h), which, by itself, did not modify the 2-DG-induced acid secretion. The increase in plasma gastrin levels induced by 2-DG was not significantly affected either by MH or by thioperamide. Under basal conditions MH (0.3 mol/kg/h) did not induce any significant change in acid secretion and in plasma gastrin levels; by contrast, thioperamide (0.1 mol/kg/h) produced a significant increase both in acid output and in plasma gastrin.These results suggest that activation of H₃ receptors can exert a negative control in stimulated acid secretion in conscious dogs, when cholinergic pathways to acid secretion are activated by 2-DG; moreover, the slight, but significant, stimulatory effect of thioperamide on basal acid output and basal plasma gastrin may be suggestive for a tonic inhibitory role of H₃ receptors in the regulation of basal acid secretion, however, a nonspecific effect of this drug cannot be excluded.Correspondence to G. Bertaccini at the above address     

H3 receptor blockade by thioperamide enhances cognition in rats without inducing locomotor sensitization

Rationale. Attention deficit hyperactivity disorder (ADHD) is currently treated with psychomotor stimulants, including methylphenidate and amphetamine. Several adverse effects are associated with these drugs, however, such as agitation and abuse. H₃ receptor antagonists are under clinical investigation for ADHD. Objectives. To investigate the potential of thioperamide, a prototypical H₃ receptor antagonist, to enhance learning and attention while inducing no effects on locomotor stimulation and sensitization, or alterations in ACTH levels. Methods. Thioperamide (1, 3, 10, 30 mg/kg) was administered prior to testing in a multi-trial, inhibitory avoidance response in rat pups (five trials separated by 1 min) to evaluate attention/cognition. Locomotor sensitization and cross-sensitization was assessed following administration of methylphenidate (3 mg/kg), cocaine (10 mg/kg), or thioperamide (1, 3, 10 mg/kg). Results. Thioperamide significantly enhanced performance of the five-trial inhibitory avoidance response with efficacy similar to that previously reported for methylphenidate. Administration of amphetamine, methylphenidate and cocaine produced significant locomotor sensitization, however. In contrast, thioperamide did not induce locomotor stimulation or sensitization, nor did it cross-sensitize to the stimulant effects of amphetamine or cocaine. The repeated administration of methylphenidate significantly elevated ACTH levels, while thioperamide did not affect this neuroendocrine endpoint. Conclusions. H₃ receptor blockade may offer a safer alternative to psychomotor stimulants for the treatment of ADHD. Electronic Publication     

Use of the H3 receptor antagonist radioligand [3H]-A-349821 to reveal in vivo receptor occupancy of cognition enhancing H3 receptor antagonists

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.     

Use of an inverse agonist radioligand [3H]A-317920 reveals distinct pharmacological profiles of the rat histamine H3 receptor

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.     

Novel heterocyclic-substituted benzofuran histamine H3 receptor antagonists: in vitro properties, drug-likeness, and behavioral activity

Three novel heterocyclic benzofurans A-688057 (1), A-687136 (2), and A-698418 (3) were profiled for their in vitro and in vivo properties as a new series of histamine H(3) receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H(3) receptors, and when profiled in vivo for CNS activity, all were found active in an animal behavioral model of attention. The compound with the most benign profile versus CNS side effects was selected for greater scrutiny of its in vitro properties and overall drug-likeness. This compound, A-688057, in addition to its potent and robust efficacy in two rodent behavioral models at blood levels ranging 0.2-19 nM, possessed other favorable features, including high selectivity for H(3) receptors (H(3), K(i)=1.5 nM) versus off-target receptors and channels (including the hERG K(+) channel, K(i)>9000 nM), low molecular weight (295), high solubility, moderate lipophilicity (logD(pH7.4)=2.05), and good CNS penetration (blood/brain 3.4x). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP(450) inhibition. Even though pharmacokinetic testing uncovered only moderate to poor oral bioavailability in rat (26%), dog (30%), and monkey (8%), and only moderate blood half-lives after i.v. administration (t(1/2) in rat of 2.9h, 1.7h in dog, 1.8h in monkey), suggesting poor human pharmacokinetics, the data overall indicated that A-688057 has an excellent profile for use as a pharmacological tool compound.     

Inhibition of noradrenaline release from the sympathetic nerves of the human saphenous vein by presynaptic histamine H3 receptors

Summary The human saphenous vein was used to examine whether presynaptic histamine receptors can modulate noradrenaline release and, if so, to determine their pharmacological characteristics. Strips of this blood vessel were incubated with [³H]noradrenaline and subsequently superfused with physiological salt solution containing desipramine and corticosterone. Electrically (2 Hz) evoked ³H overflow was inhibited by histamine and the H₃ receptor agonist R-(–)--methylhistamine. Histamine-induced inhibition of electrically evoked tritium overflow was not affected by ₂-adrenoceptor blockade by rauwolscine. S-(+)--methylhistamine (up to 10 mol/l) as well as the histamine H₁ and H₂ receptor agonists 2-(2-thiazolyl)ethylamine (up to 3 mol/l) and dimaprit (up to 30 mol/l), respectively, were ineffective. The selective histamine H₃ receptor antagonist thioperamide abolished the inhibitory effect of histamine. The histamine H₂ and H₁ receptor antagonists ranitidine and pheniramine, respectively, did not affect the histamine-induced inhibition of evoked tritium overflow. The present results are compatible with the suggestion that the sympathetic nerves of the human saphenous vein are endowed with inhibitory presynaptic histamine receptors of the H₃ class. Send offprint requests to M. Gothert at the above address     

组胺H3受体拮抗剂的研究进展

组胺H3受体不仅参与调节脑内组胺的释放、合成与代谢,还能调节其它多种神经递质的释放与代谢。它与中枢神经系统的诸多神经行为功能有密切关系。因此组胺H3受体拮抗剂的新药开发有望用于临床治疗精神行为紊乱型疾病如老年性痴呆、帕金森氏综合征等。本文简单介绍了组胺H3受体的组织分布及功能,着重综述了各种H3受体拮抗剂的研究概况。     

Participation of chemical mediators other than histamine in nasal allergy signs: a study using mice lacking histamine H(1) receptors

The purpose of this study was to investigate the involvement of chemical mediators other than histamine in nasal allergic signs using histamine H(1) receptor-deficient mice. In passively sensitized mice, antigen instillation into the nasal cavity induced significant increases in sneezing and nasal rubbing in wild-type mice, but no such increases were observed in histamine H(1) receptor-deficient mice. In actively sensitized mice, both sneezing and nasal rubbing were also significantly increased in a dose-dependent manner in both wild-type and histamine H(1) receptor-deficient mice. Histamine H(1) receptor antagonists such as cetirizine and epinastine significantly inhibited antigen-induced nasal allergic signs in wild-type mice, although the effects were incomplete. In addition, the thromboxane A(2) receptor antagonist ramatroban also inhibited these responses in wild-type mice. However, the leukotriene receptor antagonist zafirlukast showed no effects in wild-type mice. These results suggested that in the acute allergic model (passive sensitization), only histamine H(1) receptors are related to nasal signs induced by antigen, whereas in the chronic allergic model (active sensitization), both histamine H(1) receptors and thromboxane A(2) receptors were involved in the responses.     

Effects of the H<Subscript>3</Subscript> receptor inverse agonist thioperamide on cocaine-induced locomotion in mice: role of the histaminergic system and potential pharmacokinetic interactions

RATIONALE: Previous studies have shown that intraperitoneal injections of thioperamide, an imidazole-based H(3) receptor inverse agonist that enhances histamine release in the brain, potentiate cocaine-induced hyperlocomotion. The present study examined the involvement of the histaminergic system in these effects of thioperamide in mice. MATERIALS AND METHODS: We investigated whether immepip, a selective H(3) agonist, could reverse the potentiating effects of thioperamide. Moreover, the non-imidazole H(3) inverse agonist A-331440 was tested on the locomotor effects of cocaine. Using high-performance liquid chromatography with ultraviolet detection, cocaine plasma concentrations were measured to study potential drug-drug interactions between thioperamide and cocaine. Finally, thioperamide was tested on the locomotor effects of cocaine in histamine-deficient knockout mice in order to determine the contribution of histamine to the modulating effects of thioperamide. RESULTS: Thioperamide potentiated cocaine-induced hyperlocomotion in normal mice, and to a higher extent, in histamine-deficient knockout mice. A-331440 only slightly affected the locomotor effects of cocaine. Immepip did not alter cocaine-induced hyperactivity but significantly reduced the potentiating actions of thioperamide on cocaine's effects. Finally, plasma cocaine concentrations were more elevated in mice treated with thioperamide than in mice that received cocaine alone. CONCLUSIONS: The present results indicate that histamine released by thioperamide through the blockade of H(3) autoreceptors is not involved in the ability of this compound to potentiate cocaine induced-hyperactivity. Our data suggest that thioperamide, at least at 10 mg/kg, increases cocaine-induced locomotion through the combination of pharmacokinetic effects and the blockade of H(3) receptors located on non-histaminergic neurons.     

Pre-synaptic histamine H3 receptors regulate glutamate, but not GABA release in rat thalamus

We have investigated the presence of histamine H(3) receptors (H(3)Rs) on rat thalamic isolated nerve terminals (synaptosomes) and the effect of their activation on glutamate and GABA release. N-alpha-[methyl-(3)H]histamine ([(3)H]-NMHA) bound specifically to synaptosomal membranes with dissociation constant (K(d)) 0.78+/-0.20 nM and maximum binding (B(max)) 141+/-12fmol/mg protein. Inhibition of [(3)H]-NMHA binding by histamine and the H(3)R agonist immepip fit better to a two-site model, whereas for the H(3)R antagonist clobenpropit the best fit was to the one-site model. GTPgammaS (30 microM) decreased [(3)H]-NMHA binding by 55+/-4% and made the histamine inhibition fit better to the one-site model. Immepip (30 nM) induced a modest, but significant increase (113+/-2% of basal) in [(35)S]-GTPgammaS binding to synaptosomal membranes, an effect prevented by clobenpropit (1 microM) and by pre-treatment with pertussis toxin. In thalamus synaptosomes depolarisation-induced, Ca(2+)-dependent glutamate release was inhibited by histamine (1 microM, 25+/-4% inhibition) and immepip (30 nM, 38+/-5% reduction). These effects were reversed by clobenpropit (1microM). Conversely, immepip (up to 1 microM) had no effect on depolarisation-evoked [(3)H]-GABA release. Extracellular synaptic responses were recorded in the thalamus ventrobasal complex by stimulating corticothalamic afferents. H(3)R activation reduced by 38+/-7% the glutamate receptor-mediated field potentials (FPs), but increased the FP2/FP1 ratio (from 0.86+/-0.03 to 1.38+/-0.05) in a paired-pulse paradigm. Taken together, our results confirm the presence of H(3)Rs on thalamic nerve terminals and show that their activation modulates pre-synaptically glutamatergic, but not GABAergic neurotransmission.     

Molecular aspects of the histamine H3 receptor

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.     

Molecular modeling and pharmacological analysis of species-related histamine H(3) receptor heterogeneity

Presynaptic histamine H(3) receptors (H(3)R) regulate neurotransmitter release in the central nervous system, suggesting an important role for H(3) ligands in human diseases such as cognitive disorders, sleep disturbances, epilepsy, or obesity. Drug development for many of these human diseases relies upon rodent-based models. Although there is significant sequence homology between the human and rat H(3)Rs, some compounds show distinct affinity profiles. To identify the amino acids responsible for these species disparities, various mutant receptors were generated and their pharmacology studied. The N-terminal portion was shown to determine the species differences in ligand binding since a chimeric H(3)R containing N-terminal human and C-terminal rat receptor sequences exhibited similar pharmacology to the human receptor. Sequence analysis and molecular modeling studies suggested key amino acids at positions 119 and 122 in transmembrane region 3 play important roles in ligand recognition. Mutant receptors changing amino acids 119 or 122 of the human receptor to those in the rat improved ligand binding affinities and functional potencies of antagonist ligands, confirming the significant role that these amino acids play in species-related pharmacological differences. A model has been developed to elucidate the ligand receptor interactions for H(3)Rs, and pharmacological aspects of this model are described.     

Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats

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.     

Novel Benzamide-Based Histamine H3 Receptor Antagonists: The Identification of Two Candidates for Clinical Development

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