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Lin Cao, Jizheng Chen, Yaxin Wang, Yuting Yang, Jie Qing, Zihe Rao, Xinwen Chen, Zhiyong Lou
Hepatitis C virus (HCV) is a leading cause of liver disease worldwide. Although several HCV protease/polymerase inhibitors were recently approved by U.S. FDA, the combination of antivirals targeting multiple processes of HCV lifecycle would optimize anti-HCV therapy and against potential drug-resistance. Viral entry is an essential target step for antiviral development, but FDA-approved HCV entry inhibitor remains exclusive. Here we identify serotonin 2A receptor (5-HT2A R) is a HCV entry factor amendable to therapeutic intervention by a chemical biology strategy...
March 14, 2018: Protein & Cell
Fanxing Zeng, Jonathon A Nye, Ronald J Voll, Leonard Howell, Mark M Goodman
Nine pyridyloxypyridyl indole carboxamides were synthesized and displayed high affinities for 5-HT2C receptors and high selectivity over 5-HT2A and 5-HT2B . Among them, 6-methyl- N -[6-[(2-methyl-3-pyridinyl)oxy]-3-pyridinyl]1 H -indole-3-carboxamide ( 8 ) exhibits the highest 5-HT2C binding affinity ( K i = 1.3 nM) and high selectivity over 5-HT2A (∼1000 times) and 5-HT2B (∼140 times). [11 C] 8 was synthesized by palladium-catalyzed coupling reaction between pinacolboranate 16 and [11 C]CH3 I with an average radiochemical yield of 27 ± 4% ( n = 8, decay-corrected from end of [11 C]CH3 I synthesis)...
March 8, 2018: ACS Medicinal Chemistry Letters
Joshua S Elmore, Michael H Baumann
Naphthalen-1-yl-(1-pentylindol-3-yl)methanone (JWH-018) is a synthetic compound found in psychoactive "spice" products that activates cannabinoid receptors. Preclinical evidence suggests that exposure to synthetic cannabinoids increases 5-HT2A/2C receptor function in the brain, an effect which might contribute to psychotic symptoms. Here, we hypothesized that repeated exposures to JWH-018 would enhance behavioral responsiveness to the 5-HT2A/2C receptor agonist DOI. Male Sprague-Dawley rats fitted with subcutaneously (sc) temperature transponders received daily injections of JWH-018 (1...
2018: Frontiers in Psychiatry
Paloma T Birmann, Fernanda S S Sousa, Daniela H de Oliveira, Micaela Domingues, Beatriz M Vieira, Eder J Lenardão, Lucielli Savegnago
Several pathologies, such as pain and inflammation, are modulated by different pathways, making it necessary to develop drugs capable of modulating different pathways. Based on that, we investigated the antinociceptive and anti-inflammatory effect of 3-(4-chlorophenylselanyl)-1-methyl-1H-indole (CMI), as well as the systems involved in these actions. This study evaluated the antinociceptive and anti-inflammatory effects of CMI [0.0001-10mg/kg administered intragastrically (i.g.)] in the formalin, glutamate, hot plate, ear edema induced by croton oil and paw edema induced by formalin tests...
March 10, 2018: European Journal of Pharmacology
Clinton E Canal
Recent, well-controlled - albeit small-scale - clinical trials show that serotonergic psychedelics, including psilocybin and lysergic acid diethylamide, possess great promise for treating psychiatric disorders, including treatment-resistant depression. Additionally, fresh results from a deluge of clinical neuroimaging studies are unveiling the dynamic effects of serotonergic psychedelics on functional activity within, and connectivity across, discrete neural systems. These observations have led to testable hypotheses regarding neural processing mechanisms that contribute to psychedelic effects and therapeutic benefits...
March 13, 2018: Handbook of Experimental Pharmacology
Patrick D Ganzer, Carl R Beringer, Jed S Shumsky, Chiemela Nwaobasi, Karen A Moxon
Severe spinal cord injury (SCI) damages descending motor and serotonin (5-HT) fiber projections leading to paralysis and serotonin depletion. 5-HT receptors (5-HTRs) subsequently upregulate following 5-HT fiber degeneration, and dendritic density decreases indicative of atrophy. 5-HT pharmacotherapy or exercise can improve locomotor behavior after SCI. One might expect that 5-HT pharmacotherapy acts on upregulated spinal 5-HTRs to enhance function, and that exercise alone can influence dendritic atrophy. In the current study, we assessed locomotor recovery and spinal proteins influenced by SCI and therapy...
March 8, 2018: Experimental Neurology
Yi-Xiang Qi, Tian Zeng, Lei Wang, Yong-Yue Lu
The red imported fire ant, Solenopsis invicta Buren, is a dangerous invasive pest in the United States, China and other countries. Efficient division of labor is one of the main reasons for the success of this social insect. Biogenic amines are important regulators of worker division of labor in this eusocial insect, but the related molecular mechanisms are largely unknown. In this study, we identified 10 candidate biogenic amine synthetic enzyme genes and 17 candidate biogenic amine receptor genes in the genome of S...
March 8, 2018: General and Comparative Endocrinology
Dilara Nemutlu Samur, Rana Arslan, Sule Aydın, Nurcan Bektas
The purpose of this study is to assess the possible anti-allodynic and antihyperalgesic effect of valnoctamide, an amide derivative of valproic acid, at the doses of 40, 70 and 100mg/kg (i.p.) in neuropathic pain model induced by chronic constriction injury in rats, by using dynamic plantar test and plantar test (Hargreaves method), and to evaluate that the possible role of certain serotonin, noradrenergic, opioid and GABAergic receptors by pre-treatment with 1mg/kg (i.p.) ketanserin, yohimbine, naloxone and 0...
March 6, 2018: European Journal of Pharmacology
Joshua S Elmore, Ann M Decker, Agnieszka Sulima, Kenner C Rice, John S Partilla, Bruce E Blough, Michael H Baumann
2,5-Dimethoxyphenethylamines (2C compounds) are 5-HT2A/2C receptor agonists that induce hallucinogenic effects. N-methoxybenzylation of 2C compounds markedly increases their affinity for 5-HT2A receptors, and two such analogs, 2-(4-chloro-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25C-NBOMe) and 2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine (25I-NBOMe), have emerged in recreational drug markets. Here, we investigated the neuropharmacology of 25C-NBOMe and 25I-NBOMe in rats, as compared to their 2C analogs and the prototypical 5-HT2A/2C agonist 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine (DOI)...
March 1, 2018: Neuropharmacology
Landon M Klein, Nicholas V Cozzi, Paul F Daley, Simon D Brandt, Adam L Halberstadt
Substantial effort has been devoted toward understanding the psychopharmacological effects of tryptamine hallucinogens, which are thought to be mediated by activation of 5-HT2A and 5-HT1A receptors. Recently, several psychoactive tryptamines based on the N,N-diallyltryptamine (DALT) scaffold have been encountered as recreational drugs. Despite the apparent widespread use of DALT derivatives in humans, little is known about their pharmacological properties. We compared the binding affinities of DALT and its 2-phenyl-, 4-acetoxy-, 4-hydroxy-, 5-methoxy-, 5-methoxy-2-methyl-, 5-fluoro-, 5-fluoro-2-methyl-, 5-bromo-, and 7-ethyl-derivatives at 45 receptor and transporter binding sites...
February 27, 2018: Neuropharmacology
Guendalina Olivero, Massimo Grilli, Matteo Vergassola, Tommaso Bonfiglio, Cristina Padolecchia, Beatrice Garrone, Francesco Paolo Di Giorgio, Stefania Tongiani, Cesare Usai, Mario Marchi, Anna Pittaluga
Presynaptic mGlu2/3 autoreceptors exist in rat spinal cord nerve terminals as suggested by the finding that LY379268 inhibited the 15 mM KCl-evoked release of [3 H]D-aspartate ([3 H]D-Asp) in a LY341495-sensitive manner. Spinal cord glutamatergic nerve terminals also possess presynaptic release-regulating 5-HT2A heteroreceptors. Actually, the 15 mM KCl-evoked [3 H]D-Asp exocytosis from spinal cord synaptosomes was reduced by the 5-HT2A agonist (±)DOI, an effect reversed by the 5-HT2A antagonists MDL11,939, MDL100907, ketanserin and trazodone (TZD)...
February 27, 2018: Neuropharmacology
Marta Szlachta, Maciej Kuśmider, Paulina Pabian, Joanna Solich, Magdalena Kolasa, Dariusz Żurawek, Marta Dziedzicka-Wasylewska, Agata Faron-Górecka
G-protein-coupled receptor (GPCR) heterodimers are new targets for the treatment of schizophrenia. Dopamine D2 receptors and serotonin 5-HT1A and 5-HT2A receptors play an important role in neurotransmission and have been implicated in many human psychiatric disorders, including schizophrenia. Therefore, in this study, we investigated whether antipsychotic drugs (clozapine (CLZ) and haloperidol (HAL)) affected the formation of heterodimers of D2 -5-HT1A receptors as well as 5-HT1A -5-HT2A receptors. Proximity ligation assay (PLA) was used to accurately visualize, for the first time, GPCR heterodimers both at in vitro and ex vivo levels...
2018: Frontiers in Molecular Neuroscience
I Antoniadou, M Kouskou, T Arsiwala, N Singh, S R Vasudevan, T Fowler, E Cadirci, G C Churchill, T Sharp
BACKGROUND AND PURPOSE: Lithium's antidepressant action may be mediated by inhibition of inositol monophosphatase (IMPase), a key enzyme in Gq protein coupled receptor signalling. Recently, the antioxidant agent ebselen was identified as an IMPase inhibitor. Here we investigated both ebselen and lithium in models of the 5-HT2A receptor, a Gq protein coupled receptor implicated in lithium's actions. EXPERIMENTAL APPROACH: 5-HT2A receptor function was modelled in mice by measuring the behavioural (head-twitches) and cortical immediate early gene (IEG; Arc, c-fos and Erg2 mRNA) responses to 5-HT2A receptor agonist administration...
February 27, 2018: British Journal of Pharmacology
Katsunori Nonogaki, Takao Kaji
A recent report suggested that brain-derived serotonin (5-HT) is critical for maintaining weight loss induced by glucagon-like peptide-1 (GLP-1) receptor activation in rats and that 5-HT2A receptors mediate the feeding suppression and weight loss induced by GLP-1 receptor activation. Here, we show that changes in daily food intake and body weight induced by intraperitoneal administration of liraglutide, a GLP-1 receptor agonist, over 4 days did not differ between mice treated with the tryptophan hydroxylase (Tph) inhibitor p-chlorophenylalanine (PCPA) for 3 days and mice without PCPA treatment...
2018: Journal of Diabetes Research
Francis Delicata, Cristiano Bombardi, Massimo Pierucci, Roberto Di Maio, Philippe De Deurwaerdère, Giuseppe Di Giovanni
AIMS: Serotonergic (5-HT) modulation of the lateral habenula (LHb) activity is central in normal and pathologic conditions such as mood disorders. Among the multiple 5-HT receptors (5-HTRs) involved, the 5-HT2C R seems to play a pivotal role. Yet, the role of 5-HT2A Rs in the control of the LHb neuronal activity is completely unknown. METHODS: Single-cell extracellular recording of the LHb neurons was used in rats to study the effect of the general activation and blockade of the 5-HT2C R and 5-HT2A R with Ro 60-0175 and SB242084, TCB-2 and MDL11939, respectively...
February 25, 2018: CNS Neuroscience & Therapeutics
Gerard J Marek, Brian P Ramos
5-Hydroxytryptamine2A (5-HT2A ) receptors are enriched in layers I and Va of the rat prefrontal cortex and neocortex and their activation increases the frequency of glutamatergic excitatory post-synaptic potentials/currents (EPSP/Cs) onto layer V pyramidal cells. A number of other G-protein coupled receptors (GPCRs) are also enriched in cortical layers I and Va and either induce (α1 -adrenergic and orexin2 ) or suppress (metabotropic glutamate2 [mGlu2 ], adenosine A1 , μ-opioid) both 5-HT-induced EPSCs and head twitches or head shakes induced by the phenethylamine hallucinogen 2,5-dimethoxy-4-iodoamphetamine (DOI)...
2018: Frontiers in Pharmacology
M A Snider, D L Harmon, J L Klotz
Prior work using a contractility bioassay determined that the serotonin (5-HT) receptor subtype 5-HT2A is present in bovine lateral saphenous veins and plays a role in ergot alkaloid-induced vascular contraction in steers grazing endophyte-infected (Epichloë coenophiala) tall fescue (Lolium arundinaceum). Ergot alkaloids have also been shown to be vasoactive in bovine gut vasculature. To determine what 5-HT receptors are involved in vasoconstriction of gut vasculature, contractility of ruminal and mesenteric arteries and veins collected from cattle were evaluated in the presence of agonists selective for 5-HT1B (CP 93129) 5-HT1D (L-694, 247), 5-HT2A (TCB-2), 5-HT2B (BW 723C86), 5-HT4 (BIMU-8) and 5-HT7 (LP 44) receptors...
February 17, 2018: Journal of Animal Science
Hai-Quyen Tran, Youngho Lee, Eun-Joo Shin, Choon-Gon Jang, Ji Hoon Jeong, Akihiro Mouri, Kuniaki Saito, Toshitaka Nabeshima, Hyoung-Chun Kim
We investigated whether a specific serotonin (5-HT) receptor-mediated mechanism was involved in dextromethorphan (DM)-induced serotonergic behaviors. We firstly observed that the activation of 5-HT1A receptor, but not 5-HT2A receptor, contributed to DM-induced serotonergic behaviors in mice. We aimed to determine whether the upregulation of 5-HT1A receptor induced by DM facilitates the specific induction of certain PKC isoform, because previous reports suggested that 5-HT1A receptor activates protein kinase C (PKC)...
February 22, 2018: Molecular Neurobiology
Tobias Buchborn, Taylor Lyons, Thomas Knöpfel
The serotonin (5-HT) 2A receptor is the primary molecular target of serotonergic hallucinogens, which trigger large-scale perturbations of the cortex. Our understanding of how 5-HT2A activation may cause the effects of hallucinogens has been hampered by the receptor unselectivity of most of the drugs of this class. Here we used 25CN-NBOH (N-(2-hydroxybenzyl)-2,5-dimethoxy-4-cyanophenylethylamine), a newly developed selective 5-HT2A agonist, and tested it with regard to the head-twitch-response (HTR) model of 5-HT2A activity and effects on locomotion...
2018: Frontiers in Pharmacology
Anna Löfdahl, Christina Wenglén, Kristina Rydell-Törmänen, Gunilla Westergren-Thorsson, Anna-Karin Larsson-Callerfelt
Serotonin (5-hydroxytryptamine, 5-HT) is associated with several chronic pulmonary diseases, recognizing 5-HT2 receptor antagonists as potential inhibitors of tissue remodeling. However, the effects of 5-HT2 receptors, especially, 5-HT2B receptors on airway function and remodeling, are unclear. We investigated the role of 5-HT2B receptors on airway smooth muscle contractility and remodeling processes. Murine precision-cut lung slices were pre-treated with 5-HT2B receptor antagonists; EXT5, EXT9, RS127445, and PRX08066, as well as ketanserin (5-HT2A/2C receptor antagonist) (1 μM, 10 μM), prior to addition of cumulative concentrations of 5-HT to induce bronchoconstriction...
February 15, 2018: American Journal of Pathology
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