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Biochemical Pharmacology (v.73, #8)


Heterodimerization and surface localization of G protein coupled receptors by Kenneth P. Minneman (pp. 1043-1050).
G protein coupled receptors (GPCRs) are one of the largest human gene families, and are targets for many important therapeutic drugs. Over the last few years, there has been a major paradigm shift in our understanding of how these receptors function. Formerly, GPCRs were thought to exist as monomers that, upon agonist occupation, activated a heterotrimeric G protein to alter the concentrations of specific second messengers. Until recently, this relatively linear cascade has been the standard paradigm for signaling by these molecules. However, it is now clear that this model is not adequate to explain many aspects of GPCR function. We now know that many, if not most, GPCRs form homo- and/or hetero-oligomeric complexes and interact directly with intracellular proteins in addition to G proteins. It now appears that many GPCRs may not function independently, but might more accurately be described as subunits of large multi-protein signaling complexes. These observations raise many important new questions; some of which include: (1) how many functionally and pharmacologically distinct receptor subtypes exist in vivo? (2) Which GPCRs physically associate, and in what stochiometries? (3) What are the roles of individual subunits in binding ligand and activating responses? (4) Are the pharmacological or signaling properties of GPCR heterodimers different from monomers? Since these receptors are the targets for a large number of clinically useful compounds, such information is likely to be of direct therapeutic importance, both in understanding how existing drugs work, but also in discovering novel compounds to treat disease.

Keywords: Abbreviations; GPCR; G protein coupled receptor; RAMPS; receptor activity modifying proteins; AR; adrenergic receptor; ORs; olfactory receptors; PLCβ; phospholipase Cβ; PIP; 2; phosphatidylinositol 4,5 bisphosphate; IP; 3; inositol 1,4,5 trisphosphate; IP3R; IP; 3; receptor; DAG; diacylglycerolGPCRs; Dimerization; Oligomerization; Cross-talk; Pharmacology; Signaling


Structure–function of α1-adrenergic receptors by Dianne M. Perez (pp. 1051-1062).
The Easson–Stedman hypothesis provided the rationale for the first studies of drug design for the α1-adrenergic receptor. Through chemical modifications of the catecholamine core structure, the need was established for a protonated amine, a β-hydroxyl on a chiral center, and an aromatic ring with substitutions capable of hydrogen bonding. After the receptors were cloned and three α1-adrenergic receptor subtypes were discovered, drug design became focused on the analysis of receptor structure and new interactions were uncovered. It became clear that α1- and β-adrenergic receptors did not share stringent homology in the ligand-binding pocket but this difference has allowed for more selective drug design. Novel discoveries on allosterism and agonist trafficking may be used in the future design of therapeutics with fewer side effects. This review will explore past and current knowledge of the structure–function of the α1-adrenergic receptor subtypes.

Keywords: Adrenergic; Receptor; Structure; Function; Modeling; Mutagenesis; Alpha; Ligands; Drug design; Agonism; Antagonism


Central α1-adrenergic system in behavioral activity and depression by Eric A. Stone; David Quartermain; Yan Lin; Michael L. Lehmann (pp. 1063-1075).
Central α1-adrenoceptors are activated by norepinephrine (NE), epinephrine (EPI) and possibly dopamine (DA), and function in two fundamental and opposed types of behavior: (1) positively motivated exploratory and approach activities, and (2) stress reactions and behavioral inhibition. Brain microinjection studies have revealed that the positive-linked receptors are located in eight to nine brain regions spanning the neuraxis including the secondary motor cortex, piriform cortex, nucleus accumbens, preoptic area, lateral hypothalamic area, vermis cerebellum, locus coeruleus, dorsal raphe and possibly the C1 nucleus of the ventrolateral medulla, whereas the stress-linked receptors are present in at least three areas including the paraventricular nucleus of the hypothalamus, central nucleus of the amygdala and bed nucleus of the stria terminalis. Recent studies utilizing c-fos expression and mitogen-activated protein kinase activation have shown that various diverse models of depression in mice produce decreases in positive region-neural activity elicited by motivating stimuli along with increases in neural activity of stress areas. Both types of change are attenuated by various antidepressant agents. This has suggested that the balance of the two networks determines whether an animal displays depressive behavior. A central unresolved question concerns how the α1-receptors in the positive-activity and stress systems are differentially activated during the appropriate behavioral conditions and to what extent this is related to differences in endogenous ligands or receptor subtype distributions.

Keywords: α; 1; -Adrenoceptor; Depression; Neuroanatomy; Approach; Behavior; Stress


Constitutive activity and inverse agonism at the α1adrenoceptors by Susanna Cotecchia (pp. 1076-1083).
Mutations of G protein-coupled receptors (GPCR) can increase their constitutive (agonist-independent) activity. Some of these mutations have been artificially introduced by site-directed mutagenesis, others occur spontaneously in human diseases. The α1Badrenoceptor was the first GPCR in which point mutations were shown to trigger receptor activation. This article briefly summarizes some of the findings reported in the last several years on constitutive activity of the α1adrenoceptor subtypes, the location where mutations have been found in the receptors, the spontaneous activity of native receptors in recombinant as well as physiological systems. In addition, it will highlight how the analysis of the pharmacological and molecular properties of the constitutively active adrenoceptor mutants provided an important contribution to our understanding of the molecular mechanisms underlying the mechanism of receptor activation and inverse agonism.

Keywords: Abbreviations; GPCR; G protein-coupled receptor; AR; adrenoceptor; CAM; constitutively active mutant; MD; molecular dynamicsAdrenoceptors; G protein-coupled receptors; G proteins; Constitutive activity; Inverse agonism; Molecular dynamics


Histamine H3 receptor antagonists: From target identification to drug leads by P. Bonaventure; M. Letavic; C. Dugovic; S. Wilson; L. Aluisio; C. Pudiak; B. Lord; C. Mazur; F. Kamme; S. Nishino; N. Carruthers; T. Lovenberg (pp. 1084-1096).
The successful cloning and functional expression of the histamine H3 receptor in the late 1990s has greatly facilitated our efforts to identify small molecule, non-imidazole based compounds to permit the evaluation of H3 antagonists in models of CNS disorders. High-throughput screening identified several series of lead compounds, including a series of imidazopyridines, which led to JNJ-6379490, a compound with high affinity for the human H3 receptor. Analysis of structural features common to several series of non-imidazole H3 receptor ligands resulted in a pharmacophore model. This model led to the design of JNJ-5207852, a diamine-based H3 antagonist with good in vitro and in vivo efficacy but with an undesirable long half-life. However, further modifications of the template provided an understanding of the effect of structural modifications on pharmacokinetic properties, ultimately affording several additional series of compounds including JNJ-10181457, a compound with an improved pharmacokinetic profile. These compounds allowed in vivo pharmacological evaluation to show that H3 antagonists promote wakefulness, but unlike modafinil and classical psychostimultants, they do not increase locomotor activity or produce any alteration of the EEG power spectral activity in rats. H3 antagonists also increase extracellular acetylcholine and norepinephrine but not dopamine in rat frontal cortex and show efficacy in various models of learning-memory deficit. In addition, cFos immunoreactivity studies show H3 antagonists activate neuronal cells in restricted rat brain regions in contrast to widespread activation after modafinil or amphetamine treatment. Therefore, H3 antagonists are promising clinical candidates for the treatment of excessive day time sleepiness and/or cognitive disorders.

Keywords: Histamine H3 receptor; Narcolepsy; Cognition; JNJ-5207852; JNJ-10181457


Signal transduction and regulation: Are all α1-adrenergic receptor subtypes created equal? by Peter Hein; Martin C. Michel (pp. 1097-1106).
The current manuscript reviews the evidence whether and how subtypes of α1-adrenergic receptors, i.e. α1A-, α1B- and α1D-adrenergic receptors, differentially couple to signal transduction pathways and exhibit differential susceptibility to regulation. In both regards studies in tissues or cells natively expressing the subtypes are hampered because the relative expression of the subtypes is poorly controlled and the observed effects may be cell-type specific. An alternative approach, i.e. transfection of multiple subtypes into the same host cell line overcomes this limitation, but it often remains unclear whether results in such artificial systems are representative for the physiological situation. The overall evidence suggests that indeed subtype-intrinsic and cell type-specific factors interact to direct α1-adrenergic receptor signaling and regulation. This may explain why so many apparently controversial findings have been reported from various tissues and cells. One of the few consistent themes is that α1D-adrenergic receptors signal less effectively upon agonist stimulation than the other subtypes, most likely because they exhibit spontaneous internalization.

Keywords: Signal transduction; α; 1; -Adrenergic receptor; Regulation; Subtype-specific signaling; Internalization; Downregulation


Clinical implications from studies of α1 adrenergic receptor knockout mice by Taka-aki Koshimizu; Akito Tanoue; Gozoh Tsujimoto (pp. 1107-1112).
α1-Adrenergic receptors (α1-ARs) modulate a large number of physiological functions in cardiovascular and noncardiovascular tissues. Because individual members of the α1-AR family (α1A-, α1B-, and α1D-ARs) have overlapping expression profiles in most tissues, elucidation of the precise physiological roles of individual α1-AR subtypes remains a challenging task. To alleviate this constraint, a gene targeting approach has been employed to generate mutant mice lacking one or two α1-AR genes. Recent studies on these mutant mouse strains are discussed in this article, with an emphasis on the role of α1-AR in the central nervous system and lower urinary tracts. These are two major tissues of particular interest for the development of new therapeutic strategies targeted to the α1-ARs. By combining gene targeting techniques with pharmacological tools, the specific roles of α1-AR subtypes could be delineated.

Keywords: Abbreviations; α1-ARs; α1-adrenergic receptors; KO; knockout; TG; transgenic; LUT; lower urinary tract; CNS; central nervous system; BPH; benign prostatic hypertrophy; WT; wild-typeα1-Adrenergic receptors; Knockout mice; Lower urinary tract; Central nervous system; Drug development; Clinical implications


Histamine in the brain: Beyond sleep and memory by Maria Beatrice Passani; Patrizia Giannoni; Corrado Bucherelli; Elisabetta Baldi; Patrizio Blandina (pp. 1113-1122).
A few decades elapsed between the attribution of unwanted side effects of classic antihistamine compounds to the blockade of central H1 receptors, and the acceptance of the concept that the histaminergic system commands general states of metabolism and consciousness. In the early 80s, two laboratories discovered independently that histaminergic neurons are located in the posterior hypothalamus and project to the whole CNS [Panula P, Yang HY, Costa E. Histamine-containing neurons in the rat hypothalamus. Proc Natl Acad Sci 1984;81:2572–76, Watanabe T, Taguchi Y, Hayashi H, Tanaka J, Shiosaka S, Tohyama M, Kubota H, Terano Y, Wada H. Evidence for the presence of a histaminergic neuron system in the rat brain: an immunohistochemical analysis. Neurosci Lett 1983;39:249–54], suggesting a global nature of histamine regulatory effects. Recently, functional studies demonstrated that activation of the central histaminergic system alters CNS functions in both behavioral and homeostatic contexts, which include sleep and wakefulness, learning and memory, anxiety, locomotion, feeding and drinking, and neuroendocrine regulation. These actions are achieved through interactions with other neurotransmitter systems, and the interplay between histaminergic neurons and other neurotransmitter systems are becoming clear. Hence, numerous laboratories are pursuing novel compounds targeting the three known histamine receptors found in the brain for various therapeutic indications. Preclinical studies are focusing on three major areas of interest and intense research is mainly oriented towards providing drugs for the treatment of sleep, cognitive and feeding disorders. This commentary is intended to summarize some of the latest findings that suggest functional roles for the interplay between histamine and other neurotransmitter systems, and to propose novel interactions as physiological substrates that may partially underlie some of the behavioral changes observed following manipulation of the histaminergic system.

Keywords: Endocannabinoids; Acetylcholine; Hypothalamus; Microdialysis; Feeding; Fear conditioning


Differential effects of ciproxifan and nicotine on impulsivity and attention measures in the 5-choice serial reaction time test by Mark Day; Jia Bao Pan; Michael J. Buckley; Elizabeth Cronin; Peter R. Hollingsworth; Warren D. Hirst; Rachel Navarra; James P. Sullivan; Michael W. Decker; Gerard B. Fox (pp. 1123-1134).
Deficits in attention and response inhibition are apparent across several neurodegenerative and neuropsychiatric disorders for which current pharmacotherapy is inadequate. While it is difficult to model such executive processes in animals, the 5-choice serial reaction time test (5-CSRTT), which originated from the continuous performance test (CPT) in humans, may serve as a useful translational assay for efficacy in these key behavioral domains. At Wyeth and Abbott, we recently investigated the utility of employing the 5-CSRTT in adult rats. This involved training and testing groups of rats over an extended period of several months and required the animals to learn to nose-poke into one of five apertures following presentation of a brief visual stimulus in that aperture in order to obtain a food reward. When the stimulus duration was short, the rat had to pay close attention to make a correct choice—a nose-poke into the aperture with the brief visual stimulus. We evaluated nicotine and the histamine H3 receptor antagonist, ciproxifan, since compounds targeting both nicotinic and histaminergic neurotransmission are currently under investigation for treating cognitive dysfunction in ADHD, AD and schizophrenia. After approximately 12 weeks of training, rats were tested with drug when they had achieved stable performance. Nicotine (0.2, 0.4mg/kg s.c.) significantly improved accuracy and reduced errors of omission (reflecting improved attention and vigilance) when baseline performance was <90% correct. In contrast, nicotine tended to worsen accuracy when baseline performance was >90% correct. Using the same test paradigm, ciproxifan (3mg/kg i.p.) reduced premature responding, a measure of impulsivity. Under conditions of variable stimulus duration, ciproxifan also improved accuracy and decreased impulsivity. In summary, we have replicated previous findings by others of positive effects of nicotine on attention, but also showed that this is dependent on baseline performance. We also expanded on previous positive findings by others with ciproxifan on attention and both Wyeth and Abbott demonstrate for the first time decreased impulsivity with this mechanism.

Keywords: Abbreviations; 5-CSRTT; 5-choice serial reaction time test; CPT; continuous performance test; H; 3; R; histamine H; 3; receptor; SD; stimulus duration; ITI; inter-trial interval; ADHD; attention deficit hyperactivity disorder; AD; Alzheimer's disease


Regulation of α2AR trafficking and signaling by interacting proteins by Qin Wang; Lee E. Limbird (pp. 1135-1145).
The continuing discovery of new G protein-coupled receptor (GPCR) interacting proteins and clarification of the functional consequences of these interactions has revealed multiple roles for these events. Some of these interactions serve to scaffold GPCRs to particular cellular micro-compartments or to tether them to defined signaling molecules, while other GPCR–protein interactions control GPCR trafficking and the kinetics of GPCR-mediated signaling transduction. This review provides a general overview of the variety of GPCR–protein interactions reported to date, and then focuses on one prototypical GPCR, the α2AR, and the in vitro and in vivo significance of its reciprocal interactions with arrestin and spinophilin.It seems appropriate to recognize the life and career of Arthur Hancock with a summary of studies that both affirm and surprise our preconceived notions of how nature is designed, as his career-long efforts similarly affirmed the complexity of human biology and attempted to surprise pathological changes in that biology with novel, discovery-based therapeutic interventions. Dr. Hancock's love of life, of family, and of commitment to making the world a better place are a model of the life well lived, and truly missed by those who were privileged to know, and thus love, him.

Keywords: Abbreviations; GPCR; G protein-coupled receptor; α; 2; AR; α; 2; -adrenergic receptor; RGS; regulatory of G protein signaling; MAPK; mitogen-activated protein kinase; GRK; G protein-coupled receptor kinase; eIF; eukaryotic translation initiation factor; APLP; amyloid precursor like protein; APP; amyloid precursor protein; ERK; extracellular signal-regulated kinase; JNK; c-Jun amino-terminal kinase; MEF; mouse embryonic fibroblast; PP1; protein phosphatase 1; PDZ; PSD-95/Discs large/ZO-1 homologyα; 2; -Adrenergic receptor; Protein–protein interaction; Arrestin; Spinophilin; G protein-coupled receptor kinase; 14-3-3ζ


Histamine H3-receptor signaling in cardiac sympathetic nerves: Identification of a novel MAPK-PLA2-COX-PGE2-EP3R pathway by Roberto Levi; Nahid Seyedi; Ulrich Schaefer; Rima Estephan; Christina J. Mackins; Eleanor Tyler; Randi B. Silver (pp. 1146-1156).
We hypothesized that the histamine H3-receptor (H3R)-mediated attenuation of norepinephrine (NE) exocytosis from cardiac sympathetic nerves results not only from a Gαi-mediated inhibition of the adenylyl cyclase-cAMP-PKA pathway, but also from a Gβγi-mediated activation of the MAPK-PLA2 cascade, culminating in the formation of an arachidonate metabolite with anti-exocytotic characteristics (e.g., PGE2). We report that in Langendorff-perfused guinea-pig hearts and isolated sympathetic nerve endings (cardiac synaptosomes), H3R-mediated attenuation of K+-induced NE exocytosis was prevented by MAPK and PLA2 inhibitors, and by cyclooxygenase and EP3-receptor (EP3R) antagonists. Moreover, H3R activation resulted in MAPK phosphorylation in H3R-transfected SH-SY5Y neuroblastoma cells, and in PLA2 activation and PGE2 production in cardiac synaptosomes; H3R-induced MAPK phosphorylation was prevented by an anti-βγ peptide. Synergism between H3R and EP3R agonists (i.e., imetit and sulprostone, respectively) suggested that PGE2 may be a downstream effector of the anti-exocytotic effect of H3R activation. Furthermore, the anti-exocytotic effect of imetit and sulprostone was potentiated by the N-type Ca2+-channel antagonist ω-conotoxin GVIA, and prevented by an anti-Gβγ peptide. Our findings imply that an EP3R Gβγi-induced decrease in Ca2+ influx through N-type Ca2+-channels is involved in the PGE2/EP3R-mediated attenuation of NE exocytosis elicited by H3R activation. Conceivably, activation of the Gβγi subunit of H3R and EP3R may also inhibit Ca2+ entry directly, independent of MAPK intervention. As heart failure, myocardial ischemia and arrhythmic dysfunction are associated with excessive local NE release, attenuation of NE release by H3R activation is cardioprotective. Accordingly, this novel H3R signaling pathway may ultimately bear therapeutic significance in hyper-adrenergic states.

Keywords: Abbreviations; [Ca; 2+; ]; i; intraneuronal Ca; 2+; CBP; clobenpropit; COX; cyclooxygenase; DMSO; dimethyl sulfoxide; EP; 3; R; EP; 3; -receptors; H; 3; R; histamine H; 3; -receptors; I; Ca; Ca; 2+; current; MAFP; methyl arachidonyl fluorophosphonate; MAPK; mitogen activated protein kinase; NE; norepinephrine; PGE; 2; prostaglandin E; 2; PKA; protein kinase A; PLA; 2; phospholipase A; 2; VOCC; voltage-operated Ca; 2+; -channels; ω-CTX; ω-conotoxin GVIAH; 3; -receptor-induced attenuation of norepinephrine exocytosis; MAPK-PLA; 2; -COX-PGE; 2; -EP; 3; -receptor cascade; Gβγ; i; subunit; Langendorff-perfused guinea-pig hearts; Isolated sympathetic nerve endings; Cardiac synaptosomes


The brain H3-receptor as a novel therapeutic target for vigilance and sleep–wake disorders by R. Parmentier; C. Anaclet; C. Guhennec; E. Brousseau; D. Bricout; T. Giboulot; D. Bozyczko-Coyne; K. Spiegel; H. Ohtsu; M. Williams; J.S. Lin (pp. 1157-1171).
Brain histaminergic neurons play a prominent role in arousal and maintenance of wakefulness (W). H3-receptors control the activity of histaminergic neurons through presynaptic autoinhibition. The role of H3-receptor antagonists/inverse agonists (H3R-antagonists) in the potential therapy of vigilance deficiency and sleep–wake disorders were studied by assessing their effects on the mouse cortical EEG and sleep–wake cycle in comparison to modafinil and classical psychostimulants. The H3R-antagonists, thioperamide and ciproxifan increased W and cortical EEG fast rhythms and, like modafinil, but unlike amphetamine and caffeine, their waking effects were not accompanied by sleep rebound. Conversely, imetit (H3R-agonist) enhanced slow wave sleep and dose-dependently attenuated ciproxifan-induced W, indicating that the effects of both ligands involve H3-receptor mechanisms. Additional studies using knockout (KO) mice confirmed the essential role of H3-receptors and histamine-mediated transmission in the wake properties of H3R-antagonists. Thus ciproxifan produced no increase in W in either histidine-decarboxylase (HDC, histamine-synthesizing enzyme) or H1- or H3-receptor KO-mice whereas its waking effects persisted in H2-receptor KO-mice. These data validate the hypothesis that H3R-antagonists, through disinhibition of H3-autoreceptors, enhancing synaptic histamine that in turn activates postsynaptic H1-receptors promoting W. Interestingly amphetamine and modafinil, despite their potent arousal effects, appear unlikely to depend on histaminergic mechanism as their effects still occurred in HDC KO-mice. The present study thus distinguishes two classes of wake-improving agents: the first acting through non-histaminergic mechanisms and the second acting via histamine and supports brain H3-receptors as potentially novel therapeutic targets for vigilance and sleep–wake disorders.

Keywords: Abbreviations; HA; histamine; HDC; histidine decarboxylase; KO; knockout; PS; paradoxical sleep; H; 3; R-agonist; H; 3; -receptor agonist; H; 3; R-antagonist; H; 3; -receptor antagonist/inverse agonist; SWS; slow wave sleep; W; wakefulness or waking; WT; wild typeSleep–wake cycle; Histamine; H; 3; -receptor; Cortical EEG; Arousal; Vigilance; Sleep–wake disorders; Narcolepsy; Somnolence; Modafinil; Psychostimulant; Knockout mice


Histamine H3 and dopamine D2 receptor-mediated [35S]GTPγ[S] binding in rat striatum: Evidence for additive effects but lack of interactions by Marie Humbert-Claude; Séverine Morisset; Florence Gbahou; Jean-Michel Arrang (pp. 1172-1181).
The interactions in the rat striatum between H3 receptors (H3Rs) and D2 receptors (D2Rs) were investigated with the [35S]GTPγ[S] binding assay. The H3R agonist ( R)α-methylhistamine increased [35S]GTPγ[S] binding to striatal membranes with an EC50=14±5nM and a maximal effect of +19±1%. This effect was inhibited by the H3R antagonist ciproxifan with a Ki=1.0±0.3nM. The D2R agonist quinpirole increased [35S]GTPγ[S] binding to the same membranes with an EC50=1.5±0.5μM and a maximal effect of +28±2%. Its effect was blocked by haloperidol with a Ki=0.3±0.1nM. The maximal effects of the H3R and D2R agonists were additive (+46±3%). However, D2R ligands did not modify the effects of H3R ligands and vice versa. Ciproxifan behaved as an H3R inverse agonist and decreased [35S]GTPγ[S] binding. Haloperidol had no effect and did not change the inverse agonist effect of ciproxifan. Administrations for 10 days of ciproxifan (1.5mg/kg/day) or haloperidol (0.5mg/kg/day) did not change the effects of quinpirole and ( R)α-methylhistamine, respectively. These data suggest that striatal H3Rs and D2Rs do not interact through their coupling to G-proteins. However, a hyperactivity of histaminergic and dopaminergic neurons being observed in schizophrenia, the additive activations of H3Rs and D2Rs suggest that they cooperate to generate some schizophrenic symptoms. Such a postsynaptic mechanism may underlie the antipsychotic-like effects of H3R inverse agonists and supports their therapeutic interest, alone or as adjunctive treatment with neuroleptics.

Keywords: Histamine; H; 3; receptor; D; 2; receptor; Constitutive activity; G; i/o; protein; [; 35; S]GTPγS


Structurally novel histamine H3 receptor antagonists GSK207040 and GSK334429 improve scopolamine-induced memory impairment and capsaicin-induced secondary allodynia in rats by Andrew D. Medhurst; Michael A. Briggs; Gordon Bruton; Andrew R. Calver; Iain Chessell; Barry Crook; John B. Davis; Robert P. Davis; Andrew G. Foley; Teresa Heslop; Warren D. Hirst; Stephen J. Medhurst; Sandrine Ociepka; Alison Ray; Ciaran M. Regan; Becky Sargent; Joanne Schogger; Tania O. Stean; Brenda K. Trail; Neil Upton; Trevor White; Barry Orlek; David M. Wilson (pp. 1182-1194).
GSK207040 (5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1 H-3-benzazepin-7-yl)oxy]- N-methyl-2-pyrazinecarboxamide) and GSK334429 (1-(1-methylethyl)-4-({1-[6-(trifluoromethyl)-3-pyridinyl]-4-piperidinyl}carbonyl)hexahydro-1 H-1,4-diazepine) are novel and selective non-imidazole histamine H3 receptor antagonists from distinct chemical series with high affinity for human (p Ki=9.67±0.06 and 9.49±0.09, respectively) and rat (p Ki=9.08±0.16 and 9.12±0.14, respectively) H3 receptors expressed in cerebral cortex. At the human recombinant H3 receptor, GSK207040 and GSK334429 were potent functional antagonists (pA2=9.26±0.04 and 8.84±0.04, respectively versus H3 agonist-induced changes in cAMP) and exhibited inverse agonist properties (pIC50=9.20±0.36 and 8.59±0.04 versus basal GTPγS binding). Following oral administration, GSK207040 and GSK334429 potently inhibited cortical ex vivo [3H]- R-α-methylhistamine binding (ED50=0.03 and 0.35mg/kg, respectively). Functional antagonism of central H3 receptors was demonstrated by blockade of R-α-methylhistamine-induced dipsogenia in rats (ID50=0.02 and 0.11mg/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 H3 receptors may be able to reduce tactile allodynia. Novel H3 receptor antagonists such as GSK207040 and GSK334429 may therefore have therapeutic potential not only in dementia but also in neuropathic pain.

Keywords: Abbreviations; H; 3; receptor; histamine H; 3; receptor; PWT; paw withdrawal thresholdHistamine H; 3; receptor; Cognition; Scopolamine; Pain; Capsaicin; Allodynia


Molecular aspects of the histamine H3 receptor by Gerold Bongers; Remko A. Bakker; Rob Leurs (pp. 1195-1204).
The cloning of the histamine H3 receptor (H3R) cDNA in 1999 by Lovenberg et al. allowed detailed studies of its molecular aspects and indicated that the H3R can activate several signal transduction pathways including Gi/o-dependent inhibition of adenylyl cyclase, activation of phospholipase A2, Akt and the mitogen activated kinase as well as the inhibition of the Na+/H+ exchanger and inhibition of K+-induced Ca2+ mobilization. Moreover, cloning of the H3R has led to the discovery several H3R isoforms generated through alternative splicing of the H3R mRNA.The H3R 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 hH3R including its signal transduction, dimerization and the occurrence of different H3R isoforms.

Keywords: Abbreviations; H; 3; R; histamine H; 3; receptor; hH; 3; R; human histamine H; 3; receptor; PLA; 2; phospholipase A; 2; TM; transmembrane domain; GPCR; G-protein coupled receptor; NHE; Na; +; /H; +; -exchanger; PI3K; phospho-inositol-3-kinase; PTX; pertussis toxin; PKA; protein kinase KHistamine H; 3; receptor; Pharmacology; Splice variant; G protein-coupled receptor; Signal transduction; Dimerization


Identification of zebrafish histamine H1, H2 and H3 receptors and effects of histaminergic ligands on behavior by Nina Peitsaro; Maria Sundvik; Oleg V. Anichtchik; Jan Kaslin; Pertti Panula (pp. 1205-1214).
Neuronal histamine regulates several functions in the vertebrate brain. The zebrafish brain contains a widespread histaminergic system and H3 receptor ligand binding has been reported. In this study we provide evidence for the existence of histamine H1, H2 and H3 receptor genes in zebrafish. Single copies of putative histamine H1, H2 and H3 receptors were identified and cloned from the zebrafish brain. Expression analysis suggested that they are expressed in the brain and a few other tissues. Widespread distribution of zebrafish H2 receptor binding sites was detected with [125I]iodoaminopotentidine in brain sections. Zebrafish larvae were exposed to 1, 10 or 100μM of the H1 ligand pyrilamine, the H2 ligand cimetidine and the H3 ligands thioperamide and immepip for 5 days. Significant decreases in swimming distance were observed with the highest dose of all ligands, whereas cimetidine gave a significant decrease also with 1 and 10μM doses. These results provide the first molecular biological evidence for the presence of histamine receptors in zebrafish. These histamine receptors resemble those of higher vertebrates and they provide a useful model for pharmacological and behavioral studies for characterizing the functions of histamine in more detail.

Keywords: Abbreviations; α-FMH; α-fluoromethylhistidine; [; 125; I]APT; [; 125; I]iodoaminopotentidine; dpf; day post fertilization; GPCR; G-protein-coupled receptor; hpf; hour post fertilization; IC; intracellular loop; TM; transmembrane region; TMN; tuberomamillary nucleusG-protein-coupled receptors; Thioperamide; Tuberomamillary nucleus; Automated behavioral analysis; Danio rerio; Pyrilamine; Cimetidine; Immepip


Brain histamine and schizophrenia: Potential therapeutic applications of H3-receptor inverse agonists studied with BF2.649 by Xavier Ligneau; Laurent Landais; David Perrin; Johanne Piriou; Marilyne Uguen; Emmanuel Denis; Philippe Robert; Régis Parmentier; Christelle Anaclet; Jian-Sheng Lin; Aude Burban; Jean-Michel Arrang; Jean-Charles Schwartz (pp. 1215-1224).
BF2.649, a high affinity and selective non-imidazole histamine H3-receptor antagonist/inverse agonist, was found to easily enter the brain after oral administration to mice: it displayed a ratio of brain/plasma levels of about 25 when considering either Cmax or AUC values. At low oral doses (2.5–20mg/kg), it elicited in mice a dose-dependent wakening effect accompanied with a shift towards high frequency waves of the EEG, a sign of cortical activation. DOPAC/dopamine ratios were enhanced in the prefrontal cortex but not in the striatum, indicating a selective activation of a sub-population of dopaminergic neurons. BF2.649 showed significant inhibitory activity in several mouse models of schizophrenia. It reduced locomotor hyperactivity elicited by methamphetamine or dizolcipine without significantly affecting spontaneous locomotor activity when administered alone. It also abolished the apomorphine-induced deficit in prepulse inhibition.These observations suggest that H3-receptor inverse agonists/antagonists deserve attention as a novel class of antipsychotic drugs endowed with pro-cognitive properties.

Keywords: Abbreviations; ANOVA; analysis of variance; C; max; maximal concentration; AUC; area under the curve; CNS; central nervous system; GPCRs; G-protein coupled receptors; HPLC; high-performance liquid chromatography; LC; liquid chromatography; LC–MS/MS; liquid chromatography mass spectrometry; BF2.649; 1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine, hydrochloride; BF30; 1-[3-(4-chlorophenyl)propyl]-4-phenylpiperazine, hydrochloride; DOPAC; dihydroxyphenyl acetic acid; 5-HT; serotonine; 5-HIAA; 5-hydroxyindole-3-acetic acid; MK-801; dilzocilpine; CPX; ciproxifan; PCP; phencyclidine; t-MeHA; tele; -methylhistamine; APDs; antipsychotic drugs; LMA; locomotor activity; PPI; prepulse inhibition; EEG; electroencephalogram; EMG; electromyogram; W; wakefulness; SWS; slow wave sleep; PS; paradoxical sleepHistamine H; 3; receptor; Inverse agonist/antagonist; BF2.649; Sleep/wake; Schizophrenia; Locomotor activity


Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: Implications for differential drug effects on juveniles and adults by L. Charles Murrin; Jeff D. Sanders; David B. Bylund (pp. 1225-1236).
Our understanding of the development of neurotransmitter systems in the central nervous system has increased greatly over the past three decades and it has become apparent that drug effects on the developing nervous system may differ considerably from effects on the mature nervous system. Recently it has become clear there are significant differences in the effectiveness of antidepressant drug classes in children and adolescents compared to adults. Whereas the selective serotonin reuptake inhibitors are effective in treating all ages from children to adults, the tricyclic antidepressants, many of which inhibit norepinephrine reuptake, have been shown to be ineffective in treating children and adolescents even though they are effective in adults. We review here the development of the noradrenergic and serotonergic nervous systems, both in terms of neurotransmitter system markers and function. Both of these neurotransmitter systems are primary targets of antidepressant medications as well as of central nervous system stimulants. It is clear from a comparison of their development that the serotonin system reaches maturity much earlier than the norepinephrine system. We suggest this may help explain the differences in response to antidepressants in children and adolescents compared to adults. In addition, these differences suggest that drugs acting preferentially on either neurotransmitter system may impact the normal course of CNS development at different time points. Consideration of such differences in the development of neurotransmitter systems may be of significance in optimizing treatments for a variety of centrally mediated disorders.

Keywords: Norepinephrine; Serotonin; Development; Adolescent; Depression; Brain


Antagonistic targeting of the histamine H3 receptor decreases caloric intake in higher mammalian species by Kjell Malmlöf; Sven Hastrup; Birgitte Schellerup Wulff; Barbara C. Hansen; Bernd Peschke; Claus Bekker Jeppesen; Rolf Hohlweg; Karin Rimvall (pp. 1237-1242).
The main purpose of this study was to examine the effects of a selective histamine H3 receptor antagonist, NNC 38-1202, on caloric intake in pigs and in rhesus monkeys. The compound was given intragastrically (5 or 15mg/kg), to normal pigs ( n=7) and subcutaneously (1 or 0.1mg/kg) to obese rhesus monkeys ( n=9). The energy intake recorded following administration of vehicle to the same animals served as control for the effect of the compound. In addition, rhesus monkey and pig histamine H3 receptors were cloned from hypothalamic tissues and expressed in mammalian cell lines. The in vitro antagonist potencies of NNC 38-1202 at the H3 receptors were determined using a functional GTPγS binding assay.Porcine and human H3 receptors were found to have 93.3% identity at the amino acid level and the close homology between the monkey and human H3 receptors (98.4% identity) was confirmed. The antagonist potencies of NNC 38-1202 at the porcine, monkey and human histamine H3 receptors were high as evidenced by K i-values being clearly below 20nM, whereas the K i-value on the rat H3 receptor was significantly higher (56±6.0nM). NNC 38-1202, given to pigs in a dose of 15mg/kg, produced a significant ( p<0.05) reduction (55%) of calorie intake compared with vehicle alone, (132.6±10.0kcal/kgday versus 59.7±10.2kcal/kgday). In rhesus monkeys administration of 0.1 and 1mg/kg decreased ( p<0.05) average calorie intakes by 40 and 75%, respectively.In conclusion, the present study demonstrates that antagonistic targeting of the histamine H3 receptor decreases caloric intake in higher mammalian species.

Keywords: Abbreviations; i.g.; intra gastric; PCR; polymerase chain reaction; HEK-cells; human embryonic kidney-cellsHistamine; H; 3; receptor antagonist; Cloning; Caloric intake; Pigs; Monkeys


Novel heterocyclic-substituted benzofuran histamine H3 receptor antagonists: In vitro properties, drug-likeness, and behavioral activity by Marlon Cowart; Gregory A. Gfesser; Kaitlin E. Browman; Ramin Faghih; Thomas R. Miller; Ivan Milicic; John L. Baranowski; Kathleen M. Krueger; David G. Witte; Angela L. Molesky; Victoria A. Komater; Michael J. Buckley; Gilbert J. Diaz; Gerard D. Gagne; Deliang Zhou; Xiaoqing Deng; Liping Pan; Ellen M. Roberts; Marilyn S. Diehl; Jill M. Wetter; Kennan C. Marsh; Gerard B. Fox; Jorge D. Brioni; Timothy A. Esbenshade; Arthur A. Hancock (pp. 1243-1255).
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 H3 receptor antagonists. The compounds were all found to have nanomolar potency in vitro at histamine H3 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 0.2–19nM, possessed other favorable features, including high selectivity for H3 receptors (H3, K i=1.5nM) versus off-target receptors and channels (including the hERG K+ channel, K i>9000nM), low molecular weight (295), high solubility, moderate lipophilicity (logDpH7.4=2.05), and good CNS penetration (blood/brain 3.4×). In vitro toxicological tests indicated low potential for phospholipidosis, genotoxicity, and CYP450 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 ( t1/2 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.

Keywords: Histamine; H; 3; receptor; Antagonist; CNS; A-688057
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