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ACS Chemical Neuroscience

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https://www.readbyqxmd.com/read/28338324/studies-to-examine-potential-tolerability-differences-between-the-5-ht2c-receptor-selective-agonists-lorcaserin-and-cp-809101
#1
Guy A Higgins, Leonardo B Silenieks, Amy Patrick, Ines A M De Lannoy, Paul J Fletcher, Linda A Parker, Neil J MacLusky, Laura C Sullivan, Teresa A Chavera, Kelly A Berg
Lorcaserin (LOR) is a selective 5-HT2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference...
March 24, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28269984/5-ht-receptor-nomenclature-naming-names-does-it-matter-a-tribute-to-maurice-rapport
#2
Daniel Hoyer
The naming of 5-HT receptors has been challenging, especially in the early days when the concept of multiple receptors for a single neurotransmitter was considered to be unrealistic at best. Yet pharmacological (rank orders of potency in functional or biochemical settings) and transductional evidence (second messengers, electrophysiology) clearly indicated the existence of receptor families and subfamilies. The genetic revolution, with the cloning and study of recombinantly expressed receptors, and eventually the cloning of the human and other genomes have made such reservations obsolete...
March 24, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28332824/indole-substituted-benzothiazoles-and-benzoxazoles-as-selective-and-reversible-mao-b-inhibitors-for-treatment-of-parkinson-s-disease
#3
Min-Ho Nam, Moosung Park, Hyeri Park, Youngjae Kim, Seulki Yoon, Vikram Shahaji Sawant, Ji Won Choi, Jong-Hyun Park, Ki Duk Park, Sun-Joon Min, Changjoon Justin Lee, Hyunah Choo
To develop a novel, selective, and reversible MAO-B inhibitors for safer treatment of Parkinson's disease, benzothiazole and benzoxazole derivatives with indole moiety were designed and synthesized. Most of the synthesized compounds showed inhibitory activities against MAO-B and selectivity over MAO-A. The most active compound was Compound 5b, 6-fluoro-2-(1-methyl-1H-indol-5-yl)benzo[d]thiazole with an IC50 value of 29 nM with no apparent effect on MAO-A activity at 10 M. Based on the reversibility assay, Compound 5b turned out to be a fully reversible with over 95% of recovery of enzyme activity after washout of the compound...
March 23, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28272861/analysis-of-the-glutamate-agonist-ly404-039-binding-to-nonstatic-dopamine-receptor-d2-dimer-structures-and-consensus-docking
#4
Ramin Ekhteiari Salmas, Philip Seeman, Busecan Aksoydan, Ismail Erol, Isik Kantarcioglu, Matthias Stein, Mine Yurtsever, Serdar Durdagi
Dopamine receptor D2 (D2R) plays an important role in the human central nervous system and is a focal target of antipsychotic agents. The D2(High)R and D2(Low)R dimeric models previously developed by our group are used to investigate the prediction of binding affinity of the LY404,039 ligand and its binding mechanism within the catalytic domain. The computational data obtained using molecular dynamics simulations fit well with the experimental results. The calculated binding affinities of LY404,039 using MM/PBSA for the D2(High)R and D2(Low)R targets were -12...
March 22, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28324653/evaluation-of-brain-pharmacokinetic-and-neuropharmacodynamic-attributes-of-antiepileptic-drug-lacosamide-in-hepatic-and-renal-impairment-preclinical-evidence
#5
Baldeep Kumar, Manish Modi, Biman Saikia, Bikash Medhi
The knowledge of pharmacokinetic and pharmacodynamic properties of antiepileptic drugs is helpful in optimizing drug therapy for epilepsy. This study was designed to evaluate the pharmacokinetic and pharmacodynamic properties of lacosamide in experimentally induced hepatic and renal impairment in seizure animals. Hepatic or renal impairment was induced by injection of carbon tetrachloride or diclofenac sodium, respectively. After induction, the animals were administered with a single dose of lacosamide. At different time points, MES seizure recordings were done followed by isolation of plasma and brain samples for drug quantification and pharmacodynamic measurements...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28324647/metabolism-and-distribution-of-clozapine-n-oxide-implications-for-nonhuman-primate-chemogenetics
#6
Jessica Raper, J Scott Daniels, Ryan D Morrison, Leonard Howell, Jocelyne Bachevalier, Thomas Wichmann, Adriana Galvan
The use of Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) in neuroscience has rapidly expanded in rodent studies, but has lagged behind in nonhuman primate (NHP) experiments, slowing the development of this method for therapeutic use in humans. One reason for the slow adoption of DREADD technology in primates is that the pharmacokinetic properties and bioavailability of clozapine-n-oxide (CNO), the most commonly used ligand for human muscarinic (hM) DREADDs, are not fully described in primates...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28323403/discovery-of-potent-antiallodynic-agents-for-neuropathic-pain-targeting-p2x3-receptors
#7
Young-Hwan Jung, Yong-Chul Kim, Yeo Ok Kim, Hai Lin, Joong-Heui Cho, Jin-Hee Park, So-Deok Lee, Jinsu Bae, Koon Mook Kang, Yoon Gyoon Kim, Ae Nim Pae, Hyojin Ko, Chul-Seung Park, Myung Ha Yoon
Antagonism of the P2X3 receptor is one of the potential therapeutic strategies for the management of neuropathic pain because P2X3 receptors are predominantly localized on small to medium diameter C- and Aδ-fiber primary afferent neurons, which are related to the pain-sensing system. In this study, 5-hydroxy pyridine derivatives were designed, synthesized, and evaluated for their in vitro biological activities by two-electrode voltage clamp assay at hP2X3 receptors. Among the novel hP2X3 receptor antagonists, intrathecal treatment of compound 29 showed parallel efficacy with pregabalin (calcium channel modulator) and higher efficacy than AF353 (P2X3 receptor antagonist) in the evaluation of its antiallodynic effects in spinal nerve ligation rats...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28323401/zinc-and-copper-effects-on-stability-of-tubulin-and-actin-networks-in-dendrites-and-spines-of-hippocampal-neurons
#8
Laura Perrin, Stephane Roudeau, Asuncion Carmona, Florelle Domart, Jennifer D Petersen, Sylvain Bohic, Yang Yang, Peter Cloetens, Richard Ortega
Zinc and copper ions can modulate the activity of glutamate-receptors. However, labile zinc and copper ions likely represent only the tip of the iceberg and other neuronal functions are suspected for these metals in their bound state. We performed synchrotron X-ray fluorescence imaging with 30 nm resolution to image total biometals in dendrites and spines from hippocampal neurons. We found that zinc is distributed all along the dendrites while copper is mainly pinpointed within the spines. In spines, zinc content is higher within the spine head while copper is higher within the spine neck...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28322043/-sup-18-sup-f-fluoro-hydroxyphenethylguanidines-efficient-synthesis-and-comparison-of-two-structural-isomers-as-radiotracers-of-cardiac-sympathetic-innervation
#9
Yong-Woon Jung, Keun Sam Jang, Guie Gu, Robert A Koeppe, Phillip S Sherman, Carole A Quesada, David M Raffel
Fluorine-18 labeled phenethylguanidines are currently under development in our laboratory as radiotracers for quantifying regional cardiac sympathetic nerve density using PET imaging techniques. In this study, we report an efficient synthesis of <sup>18</sup>F-hydroxyphenethylguanidines consisting of nucleophilic aromatic [<sup>18</sup>F]fluorination of a protected diaryliodonium salt precursor followed by a single deprotection step to afford the desired radiolabeled compound. This approach has been shown to reliably produce 4-[<sup>18</sup>F]fluoro-<i>m</I>-hydroxyphenethylguanidine ([<sup>18</sup>F]4F-MHPG, [<sup>18</sup>F]<b>1</b>) and its structural isomer 3-[<sup>18</sup>F]fluoro-<i>p</i>-hydroxyphenethylguanidine ([<sup>18</sup>F]3F-PHPG, [<sup>18</sup>F]<b>2</b>) with good radiochemical yields...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28290668/surface-assay-for-specific-detection-of-soluble-amyloid-oligomers-utilizing-pronucleon-peptides-instead-of-antibodies
#10
Evgenia G Matveeva, Jonathan R Moll, Mariam M Khan, Richard B Thompson, Richard O Cliff
Immunoassays such as enzyme-linked immunosorbent assays (ELISAs) are widely used for diagnostics; however, antibodies as detection reagents may be insufficiently selective and have other shortcomings. We present a novel non-antibody-based detection method based on binding target molecules to peptides (used as recognition molecules): a surface assay for A-β oligomers employing a peptide comprising amino acid residues of the human β-amyloid protein (Pronucleon peptide) as the capture agent. For the sake of convenience, we term this the "Pronucleon peptide-linked immunosorbent assay", or PLISA...
March 21, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28272863/serotonin-transporter-independent-actions-of-the-antidepressant-vortioxetine-as-revealed-using-the-sert-met172-mouse
#11
Alex G Nackenoff, Linda D Simmler, Nicole L Baganz, Alan L Pehrson, Connie Sánchez, Randy D Blakely
Selective serotonin (5-HT, SERT) reuptake inhibitors (SSRIs) are the most commonly prescribed treatments for depression. However, they have delayed efficacy and can induce side-effects that can encourage discontinuation. Recently, agents have been developed, including vortioxetine (Trintellix), that augment SERT blockade with interactions at other targets. At therapeutic doses, vortioxetine interacts with SERT as well as 5-HT1A, 5-HT1B, 5-HT3, and 5-HT7 receptors. We assessed the SERT-dependency of vortioxetine action using the SERT Met172 mouse model, which disrupts high-affinity interactions of many antidepressants with the transporter...
March 20, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28290665/kaplan-meier-meets-chemical-kinetics-intrinsic-rate-of-sod1-amyloidogenesis-decreased-by-subset-of-als-mutations-and-cannot-fully-explain-age-of-disease-onset
#12
Alireza Abdolvahabi, Yunhua Shi, Sanaz Rasouli, Corbin M Croom, Amir Aliyan, Angel A Marti, Bryan F Shaw
Over 150 mutations in SOD1 (superoxide dismutase-1) cause amyotrophic lateral sclerosis (ALS), presumably by accelerating SOD1 amyloidogenesis. Like many nucleation processes, SOD1 fibrillization is stochastic (in vitro), which inhibits determination of aggregation rates (and obscures whether rates correlate with patient phenotypes). Here, we diverged from classical chemical kinetics and used Kaplan-Meier estimators to quantify the probability of apo-SOD1 fibrillization (in vitro) from ~ 10(3) replicate amyloid assays of wild-type (WT) SOD1 and nine ALS variants...
March 14, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28290664/differential-pharmacophore-definition-of-the-camp-binding-sites-of-ncs-rapgef2-pka-and-epac-in-neuroendocrine-cells-using-an-adenine-based-scaffold
#13
Andrew Clayton Emery, Ryan A Alvarez, Maribeth V Eiden, Wenqin Xu, Fabrice G Simeon, Lee E Eiden
We recently reported that the adenylate cyclase (AC) inhibitor SQ22,536 (9-tetrahydrofuranyl-adenine) also has inhibitory activity against the neuroendocrine-specific neuritogenic cAMP sensor-Rapgef2 (NCS-Rapgef2), a guanine nucleotide exchanger and activator for the small effector GTPase Rap1. Cell-based assays that distinguish signaling through the three intracellular cAMP sensors NCS-Rapgef2, exchange protein activated by cAMP (Epac), and protein kinase A (PKA), as well as AC, were used. These, collectively, assess the activities of adenine (6-amino-purine) derivatives modified at several positions to enhance selectivity for NCS-Rapgef2 by decreasing affinity for adenylate cyclase (AC), without increasing affinity for PKA or Epac...
March 14, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28288510/diverse-effects-of-gut-derived-serotonin-in-intestinal-inflammation
#14
Md Sharif Shajib, Adriana Baranov, Waliul Islam Khan
The gut is the largest producer of serotonin or 5-hydroxytryptamine (5-HT) in the human body, and 5-HT has been recognized as an important signaling molecule in the gut for decades. There are two distinct sources of enteric 5-HT. Mucosal 5-HT is predominantly produced by enterochromaffin (EC) cells of the gastrointestinal (GI) tract and neuronal 5-HT in the gut is produced by serotonergic neurons of the enteric nervous system (ENS). The quantity of mucosal 5-HT produced vastly eclipses the amount of neuronal 5-HT in the gut...
March 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28287691/effects-of-housing-on-methamphetamine-induced-neurotoxicity-and-spatial-learning-and-memory
#15
Arnold Gutierrez, Sarah A Jablonski, Robyn M Amos-Kroohs, Anna C Barnes, Michael T Williams, Charles V Vorhees
Severe stress potentiates methamphetamine (MA) neurotoxicity. However, whether moderate stress increases or decreases the neurotoxic effects of MA is unknown. We assessed the effects of MA (4 x 10 mg/kg at 2 h intervals) in combination with prior barren-cage housing in adult male Sprague-Dawley rats on monoamines and glial fibrillary acid protein (GFAP) in one cohort and spatial learning and memory in the Morris water maze in another cohort. MA reduced dopamine (DA) and serotonin (5-HT) in the neostriatum and nucleus accumbens, 5-HT in the hippocampus, and increased GFAP in neostriatum and nucleus accumbens compared with saline controls...
March 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28287253/the-rodent-forced-swim-test-measures-stress-coping-strategy-not-depression-like-behavior
#16
Kathryn G Commons, Aram B Cholanians, Jessica A Babb, Daniel G Ehlinger
The Forced Swim Test (FST) measures coping strategy to an acute inescapable stress and thus provides unique insight into the neural limb of the stress response. Stress, particularly chronic stress, is a contributing factor to depression in humans and depression is associated with altered response to stress. In addition, drugs that are effective antidepressants in humans typically promote active coping strategy in the FST. As a consequence passive coping in the FST has become loosely equated with depression and is often referred to as 'depression-like' behavior...
March 13, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28281745/n-methyl-mesoporphyrin-ix-as-an-effective-probe-for-monitoring-alzheimer-s-disease-%C3%AE-amyloid-aggregation-in-living-cells
#17
Meng Li, Andong Zhao, Jinsong Ren, Xiaogang Qu
Formation of amyloid fibrils by amyloid-β peptide (Aβ) is an important step in Alzheimer's disease (AD) pro-gression. Screening and designing new molecules which can monitor amyloidosis process especially in cells are diagnostically and therapeutically important. Utilizing Thioflavin T (ThT), the commonly used amyloid dye, is the most standardized way to monitor amyloid. However, with the green fluorescence emission and small Stokes shift, the fluorescence of ThT can overlap with that arising from other intrinsic fluorescent components in the cells, making it not suitable for detection of protein aggregates in vivo...
March 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28263550/immunochemical-detection-of-%C3%AE-synuclein-autoantibodies-in-parkinson-s-disease-correlation-between-plasma-and-cerebrospinal-fluid-levels
#18
Istvan Horvath, Igor A Iashchishyn, Lars Forsgren, Ludmilla A Morozova-Roche
Autoantibodies to Parkinson's disease (PD) amyloidogenic protein, α-synuclein, were recognized as a prospective biomarker for early disease diagnostics, yet there is inconsistency in previous reports, potentially related to PD status. Therefore, plasma and cerebrospinal fluid (CSF) of the cross-sectional cohort of 60 individuals, including recently diagnosed PD patients with mild and moderate PD and age-matched controls, were examined by enzyme-linked immunosorbent assay (ELISA). Nonparametric statistics was used for data analysis...
March 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28165217/calcium-assists-dopamine-release-by-preventing-aggregation-on-the-inner-leaflet-of-presynaptic-vesicles
#19
Sini Mokkila, Pekka A Postila, Sami Rissanen, Hanna Juhola, Ilpo Vattulainen, Tomasz Róg
In this study, the dopamine-lipid bilayer interactions were probed with three physiologically relevant ion compositions using atomistic molecular dynamics simulations and free energy calculations. The in silico results indicate that calcium is able to decrease significantly the binding of dopamine to a neutral (zwitterionic) phosphatidylcholine lipid bilayer model mimicking the inner leaflet of a presynaptic vesicle. We argue that the observed calcium-induced effect is likely in crucial role in the neurotransmitter release from the presynaptic vesicles docked in the active zone of nerve terminals...
March 10, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28278376/stapled-voltage-gated-calcium-channel-cav-%C3%AE-interaction-domain-aid-peptides-act-as-selective-protein-protein-interaction-inhibitors-of-cav-function
#20
Felix Findeisen, Marta Campiglio, Hyunil Jo, Fayal Abderemane-Ali, Christine H Rumpf, Lianne Pope, Nathan D Rossen, Bernhard E Flucher, William F DeGrado, Daniel L Minor
For many voltage-gated ion channels (VGICs) creation of a properly functioning ion channel requires the formation of specific protein protein interactions between the transmembrane pore-forming subunits and cytoplasmic accessory subunits. Despite the importance of such protein-protein interactions in VGIC function and assembly, their potential as sites for VGIC modulator development has been largely overlooked. Here, we develop meta xylyl (m xylyl) stapled peptides that target a prototypic VGIC high affinity protein-protein interaction, the interaction between the voltage-gated calcium channel (CaV) pore forming subunit α interaction domain (AID) and cytoplasmic β subunit (CaVβ)...
March 9, 2017: ACS Chemical Neuroscience
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