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Histamine H3

Satoshi Tanaka, Minoru Sakaguchi, Hiroki Yoneyama, Yoshihide Usami, Shinya Harusawa
Histamine is involved in various physiological functions, including its neurotransmitter actions in the central nervous system and its action as a causative agent of inflammation, allergic reactions, and gastric acid secretions. Histamine expression and biosynthesis have been detected in breast cancer cells. It was recently suggested that the histamine H3 receptor (H3R) plays a role in the proliferation of breast cancer cells. We recently developed the non-imidazole H3R antagonist OUP-186 which exhibited a potent and selective human H3R antagonistic activity as well as no activity against the human histamine H4 receptor (H4R)...
October 21, 2016: Biochemical and Biophysical Research Communications
Nayeli Rivera-Ramírez, Wilber Montejo-López, María-Cristina López-Méndez, Agustín Guerrero-Hernández, Anayansi Molina-Hernández, Ubaldo García-Hernández, José-Antonio Arias-Montaño
The histamine H3 receptor (H3R) is abundantly expressed in the Central Nervous System where it regulates several functions pre and postsynaptically. H3Rs couple to Gαi/o proteins and trigger or modulate several intracellular signaling pathways, including the cAMP/PKA pathway and the opening of N- and P/Q-type voltage-gated Ca(2+) channels. In transfected cells, activation of the human H3R of 445 amino acids (hH3R445) results in phospholipase C (PLC) stimulation and release of Ca(2+) from intracellular stores...
October 12, 2016: Neurochemistry International
Róbert Kiss, György M Keserű
The application of structure-based drug discovery in histamine receptor projects was previously hampered by the lack of experimental structures. The publication of the first X-ray structure of the histamine H1 receptor has been followed by several successful virtual screens and binding site analysis studies of H1-antihistamines. This structure together with several other recently solved aminergic G-protein coupled receptors (GPCRs) enabled the development of more realistic homology models for H2, H3 and H4 receptors...
October 5, 2016: Expert Opinion on Drug Discovery
Esmaeal Tamaddonfard, Amir Erfanparast, Hamid Ghasemi, Farzin Henareh-Chareh, Mansoor Hadidi, Navideh Mirzakhani, Sahar Seyedin, Mina Taati, Reza Salighedar, Sara Salimi, Farshad Safaei
Histamine receptors are involved in supraspinal modulation of pain. In the present study, we investigated the effects of microinjection of histamine H1, H2 and H3 receptor antagonists and agonists into the ventral posteromedial (VPM) nucleus of the thalamus on two models of trigeminal pain. Right and left sides of VPM were implanted with two guide cannulas. Corneal pain was induced by local corneal surface application of hypertonic saline and the number of eye wipes was recorded. The duration of face rubbing, as an orofacial pain measure, was recorded after subcutaneous (s...
September 29, 2016: European Journal of Pharmacology
Hiroki Yoneyama, Daisuke Yamamoto, Atsushi Yamatodani, Shinya Harusawa
S-Alkyl-N-alkylisothiourea compounds, which contain various cyclic amines, were synthesized using 3-phenylpropionyl isothiocyanate (PPI) to discover novel non-imidazole histamine H3 receptor (H3R) antagonists. The synthetic route was improved remarkably by using 2-nitrophenylacetyl isothiocyanate (NPAI). Among the synthesized compounds, N-[4-(4-chlorophenyl)butyl]-S-[3-piperidin-1-yl)propyl]isothiourea (1k, OUP-186) exhibited potent and selective antagonism against human H3R but not human H4R, in vitro. Of particular interest, they did not show antagonism for the histamine release in rat brain microdialysis in vivo, suggesting species-selective differences in antagonist affinities...
2016: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
Natasha L Lethbridge, Paul L Chazot
Dementia with Lewy bodies (DLB) is a serious age-dependent human neurodegenerative disease, with multiple debilitating symptoms, including dementia, psychosis and significant motor deficits, but with little or no effective treatments. This comparative ligand autoradiographical study has quantified histamine H3 receptors (H3R) in a series of major cortical and basal ganglia structures in human DLB and Alzheimer's (AD) post-mortem cases using the highly selective radioligand, [(3)H] GSK189254. In the main, the levels of H3 receptor were largely preserved in DLB cases when compared with aged-matched controls...
August 31, 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Masayuki Hanyu, Kazunori Kawamura, Makoto Takei, Kenji Furutsuka, Satoshi Shiomi, Tomoya Fujishiro, Masanao Ogawa, Nobuki Nengaki, Hiroki Hashimoto, Toshimitsu Fukumura, Ming-Rong Zhang
INTRODUCTION: Recently, 6-[(1-cyclobutylpiperidin-4-yl)oxy]-1-(6-[(11)C]methoxypyridin-3-yl)-3,4-dihydroquinolin-2(1H)-one ([(11)C]TASP457, [(11)C]2) has been developed as a novel PET ligand for histamine H3 receptors in brain. [(11)C]2 is potentially suitable for imaging H3 receptors in rat and monkey brains, which has motivated us to perform first-in-human study of [(11)C]2 for qualifying H3 receptors in human brain. In this paper, we report an efficient radiosynthesis of [(11)C]2 to obtain sufficient radioactivity and high quality for clinical application...
August 10, 2016: Nuclear Medicine and Biology
Christian Brabant, Yana Charlier, Maria Elisa Serrano Navacerrada, Livia Alleva, Ezio Tirelli
Previous studies have demonstrated that the histamine H3 receptor inverse agonist thioperamide potentiates the stimulant and rewarding effects of cocaine. However, these potentiating effects of thioperamide do not necessarily result from H3 receptor blockade since thioperamide is an imidazole-based compound capable of enhancing plasma cocaine concentrations by blocking cytochrome P450 activity. In contrast, Pitolisant is a non-imidazole H3 receptor inverse agonist that has already been tested in clinical trials but it remains to be determined whether this compound also potentiates the behavioral effects of cocaine...
August 26, 2016: European Journal of Pharmacology
Bassem Sadek, Nadia Khan, Fouad H Darras, Steffen Pockes, Michael Decker
Both the acetylcholine esterase (AChE) and the histamine H3 receptor (H3R) are involved in the metabolism and modulation of acetylcholine release and numerous other centrally acting neurotransmitters. Hence, dual-active AChE inhibitors (AChEIs) and H3R antagonists hold potential to treat cognitive disorders like Alzheimer's disease (AD). The novel dual-acting AChEI and H3R antagonist 7-(3-(piperidin-1-yl)propoxy)-2,3-dihydropyrrolo[2,1-b]quinazolin-9(1H)-one (UW-MD-72) shows excellent selectivity profiles over the AChE's isoenzyme butyrylcholinesterase (BChE) as well as high and balanced in-vitro affinities at both AChE and hH3R with IC50 of 5...
October 15, 2016: Physiology & Behavior
Bianca C L F Távora, Louise F Kimura, Marta M Antoniazzi, Thiago M Chiariello, Eliana L Faquim-Mauro, Katia C Barbaro
Bites caused by Scolopendra viridicornis centipede are mainly characterized by burning pain, paresthesia and edema. On this regard, the aim of this work was to study the involvement of mast cells and histamine in edema induced by Scolopendra viridicornis (Sv) centipede venom. The edema was analyzed on mice paws. The mice were pretreated with cromolyn (mast cell degranulation inhibitor) and antagonists of histamine receptors, such as promethazine (H1R), cimetidine (H2R) and thioperamide (H3/H4R). The analyses were carried out at different times after the injection of Sv venom (15 μg) or PBS in the footpad of mice...
October 2016: Toxicon: Official Journal of the International Society on Toxinology
Gustavo Nieto-Alamilla, Ricardo Márquez-Gómez, Ana-Maricela García-Gálvez, Guadalupe-Elide Morales-Figueroa, José-Antonio Arias-Montaño
Among the four G protein-coupled receptors (H1-H4) identified as mediators of the biologic effects of histamine, the H3 receptor (H3R) is distinguished for its almost exclusive expression in the nervous system and the large variety of isoforms generated by alternative splicing of the corresponding mRNA. Additionally, it exhibits dual functionality as autoreceptor and heteroreceptor, and this enables H3Rs to modulate the histaminergic and other neurotransmitter systems. The cloning of the H3R cDNA in 1999 by Lovenberg et al...
November 2016: Molecular Pharmacology
Tomomitsu Miyasaka, Kaori Okuyama-Dobashi, Chiaki Masuda, Shunya Iwami, Miki Sato, Hirokazu Mizoguchi, Tasuku Kawano, Yuichi Ohkawara, Shinobu Sakurada, Motoaki Takayanagi, Isao Ohno
BACKGROUND: Psychological stress is one of the major risk factors for asthma exacerbation. Although histamine in the brain acts as an excitatory and inhibitory neurotransmitter associated with psychological stress, the contribution of brain histamine to psychological stress-induced exacerbation of asthma remains unclear. The objective of this study was to investigate the role of histamine receptors in the CNS on stress induced asthma aggravation. METHODS: We monitored the numbers of inflammatory cells and interleukin (IL)-13 levels in bronchoalveolar lavage fluid, airway responsiveness to inhaled methacholine, mucus secretion in airway epithelial cells, and antigen-specific IgE contents in sera in a murine model of stress-induced asthma treated with epinastine (an H1R antagonist), thioperamide (an H3/4R antagonist), or solvent...
September 2016: Allergology International: Official Journal of the Japanese Society of Allergology
Maximiliano Rapanelli, Luciana R Frick, Kyla D Horn, Rivka C Schwarcz, Vladimir Pogorelov, Angus C Nairn, Christopher Pittenger
The basal ganglia have a central role in motor patterning, habits, motivated behaviors, and cognition as well as in numerous neuropsychiatric disorders. Receptors for histamine, especially the H3 receptor (H3R), are highly expressed in the striatum, the primary input nucleus of the basal ganglia, but their effects on this circuitry have been little explored. H3R interacts with dopamine (DA) receptors ex vivo; the nature and functional importance of these interactions in vivo remain obscure. We found H3R activation with the agonist R-(-)-α-methylhistamine to produce a unique time- and cell type-dependent profile of molecular signaling events in the striatum...
September 30, 2016: Journal of Biological Chemistry
Damijana M Jurič, Mojca Kržan, Metoda Lipnik-Stangelj
Astrocytes support the brain through numerous functional interactions in health and disease. The recent advances in our knowledge of astrocyte involvement in various neurological disorders raised up several questions about their role and functioning in the central nervous system. From the evidence discussed in this review, we show that histamine importantly influences the main astrocytic activities such as ion homeostasis, energy metabolism, neurotransmitter clearance, neurotrophic activity and immune response...
September 2016: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
Dorota Łażewska, Jakub Jończyk, Marek Bajda, Natalia Szałaj, Anna Więckowska, Dawid Panek, Caitlin Moore, Kamil Kuder, Barbara Malawska, Katarzyna Kieć-Kononowicz
In recent years, multitarget-directed ligands have become an interesting strategy in a search for a new treatment of Alzheimer's disease. Combination of both: a histamine H3 receptor antagonist/inverse agonist and a cholinesterases inhibitor in one molecule could provide a new therapeutic opportunity. Here, we present biological evaluation of histamine H3 receptor ligands-chlorophenoxyalkylamine derivatives against cholinesterases: acetyl- and butyrylcholinesterase. The target compounds showed cholinesterase inhibitory activity in a low micromolar range...
August 15, 2016: Bioorganic & Medicinal Chemistry Letters
Gabriela Flores-Balter, Héctor Cordova-Jadue, Alessandra Chiti-Morales, Carolyne Lespay, Pablo Espina-Marchant, Romina Falcon, Noemi Grinspun, Jessica Sanchez, Diego Bustamante, Paola Morales, Mario Herrera-Marschitz, José L Valdés
Perinatal asphyxia (PA) is associated with long-term neuronal damage and cognitive deficits in adulthood, such as learning and memory disabilities. After PA, specific brain regions are compromised, including neocortex, hippocampus, basal ganglia, and ascending neuromodulatory pathways, such as dopamine system, explaining some of the cognitive disabilities. We hypothesize that other neuromodulatory systems, such as histamine system from the tuberomammillary nucleus (TMN), which widely project to telencephalon, shown to be relevant for learning and memory, may be compromised by PA...
October 15, 2016: Behavioural Brain Research
Yahiya Y Syed
Pitolisant (Wakix™) is an inverse agonist of the histamine H3 receptor that is being developed by Bioproject. Oral pitolisant is approved in the EU for the treatment of narcolepsy with or without cataplexy in adults. Pitolisant has received a Temporary Authorization of Use in France for this indication in case of treatment failure, intolerance or contraindication to currently available treatment. Pitolisant has orphan drug designation in the EU and the USA. In the pivotal HARMONY I trial, pitolisant significantly decreased excessive daytime sleepiness versus placebo in adults with narcolepsy with or without cataplexy (primary endpoint)...
September 2016: Drugs
Lokesh Verma, Nishant S Jain
Intrigued by the report demonstrating an increase in brain histamine levels by ethanol administration and central histamine transmission to affect the anxiety related behaviors, the present study examined the permissive role of central histaminergic transmission in the acute anxiolytic-like effect of the ethanol on elevated plus maze (EPM) in mice. Results demonstrated that prior administration of the agents that are known to enhance the brain histamine transmission, i.e. low dose of histamine (0.1μg/mouse, i...
October 15, 2016: Behavioural Brain Research
Burcin Altinbas, Gokcen Guvenc, Leman G Erkan, Tuncay Ilhan, Nasir Niaz, Murat Yalcin
The purpose of the current study is to investigate the functional connections between the central histaminergic and cholinergic systems at NTS level in hypotensive condition. Experiments were carried out in male Wistar Albino rats. The hypotension was achieved by withdrawing a total volume of 1.5ml blood/100g bodyweight over a period of 10min. A microdialysis study was performed in NTS area to measure extracellular ACh and Ch levels. The hemorrhage produced a severe and long-lasting decrease in mean arterial blood pressure (MAP) and increase in extracellular ACh and Ch levels in NTS...
July 1, 2016: Brain Research
Mar Rodríguez-Ruiz, Estefanía Moreno, David Moreno-Delgado, Gemma Navarro, Josefa Mallol, Antonio Cortés, Carme Lluís, Enric I Canela, Vicent Casadó, Peter J McCormick, Rafael Franco
Alzheimer's disease (AD) is a neurodegenerative disorder causing progressive memory loss and cognitive dysfunction. Anti-AD strategies targeting cell receptors consider them as isolated units. However, many cell surface receptors cooperate and physically contact each other forming complexes having different biochemical properties than individual receptors. We here report the discovery of dopamine D1, histamine H3, and N-methyl-D-aspartate (NMDA) glutamate receptor heteromers in heterologous systems and in rodent brain cortex...
July 1, 2016: Molecular Neurobiology
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