71,476 results match your criteria antagonists ion

Positive allosteric modulation of NMDA receptors: mechanisms, physiological impact and therapeutic potential.

J Physiol 2021 Aug 2. Epub 2021 Aug 2.

Institut de Biologie de l'Ecole Normale Supérieure (IBENS), Ecole Normale Supérieure, Université PSL, CNRS, INSERM, Paris, F-75005, France.

NMDA receptors (NMDARs) are glutamate-gated ion channels that play key roles in synaptic transmission and plasticity. Both hyper- and hypo-activation of NMDARs are deleterious to neuronal function. In particular, NMDAR hypofunction is involved in a wide range of neurological and psychiatric conditions like schizophrenia, intellectual disability, age-dependent cognitive decline or Alzheimer's disease. Read More

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Therapeutic Targeting of 7 Nicotinic Acetylcholine Receptors.

Pharmacol Rev 2021 Jul;73(3):1118-1149

Departments of Pharmacology and Therapeutics (R.L.P) and Chemistry (N.A.H.), University of Florida, Gainesville, FL.

The 7-type nicotinic acetylcholine receptor is one of the most unique and interesting of all the members of the cys-loop superfamily of ligand-gated ion channels. Since it was first identified initially as a binding site for -bungarotoxin in mammalian brain and later as a functional homomeric receptor with relatively high calcium permeability, it has been pursued as a potential therapeutic target for numerous indications, from Alzheimer disease to asthma. In this review, we discuss the history and state of the art for targeting 7 receptors, beginning with subtype-selective agonists and the basic pharmacophore for the selective activation of 7 receptors. Read More

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Knockdown of Mitogen-Activated Protein Kinase Kinase 3 Negatively Regulates Hepatitis A Virus Replication.

Int J Mol Sci 2021 Jul 10;22(14). Epub 2021 Jul 10.

Division of Gastroenterology and Hepatology, Department of Medicine, Nihon University School of Medicine, 30-1 Oyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Zinc chloride is known to be effective in combatting hepatitis A virus (HAV) infection, and zinc ions seem to be especially involved in Toll-like receptor (TLR) signaling pathways. In the present study, we examined this involvement in human hepatoma cell lines using a human TLR signaling target RT-PCR array. We also observed that zinc chloride inhibited mitogen-activated protein kinase kinase 3 (MAP2K3) expression, which could downregulate HAV replication in human hepatocytes. Read More

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Future prophylactic treatments in migraine: Beyond anti-CGRP monoclonal antibodies and gepants.

Rev Neurol (Paris) 2021 Jul 19. Epub 2021 Jul 19.

Danish Headache Center, Department of Neurology, Rigshospitalet Glostrup, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; Danish Knowledge Center on Headache Disorders, Glostrup, Denmark. Electronic address:

Migraine is ranked as a leading cause of years lived with disability among all neurological disorders. Therapies targeting the calcitonin gene-related peptide (CGRP) signaling pathway, including monoclonal antibodies against the receptor or ligand and small molecule CGRP receptor antagonists (gepants), are today approved for migraine prophylaxis with additional compounds expected to be introduced to the market soon. In this review, we consider other putative prophylactic migraine drugs in development, including compounds targeting G-protein coupled receptors, glutamate, ion channels, and neuromodulatory devices. Read More

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Motions around conserved helical weak spots facilitate GPCR activation.

Proteins 2021 Jul 17. Epub 2021 Jul 17.

CMBI, Radboudumc, Nijmegen, Netherlands.

G protein-coupled receptors (GPCRs) participate in most physiological processes and are important drug targets in many therapeutic areas. Recently, many GPCR X-ray structures became available, facilitating detailed studies of their sequence-structure-mobility-function relations. We show that the functional role of many conserved GPCR sequence motifs is to create weak spots in the transmembrane helices that provide the structural plasticity necessary for ligand binding and signaling. Read More

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Piezo Channels: Awesome Mechanosensitive Structures in Cellular Mechanotransduction and Their Role in Bone.

Int J Mol Sci 2021 Jun 16;22(12). Epub 2021 Jun 16.

Lab for Bone Metabolism, Key Lab for Space Biosciences and Biotechnology, School of Life Sciences, Northwestern Polytechnical University, Xi'an 710072, China.

Piezo channels are mechanosensitive ion channels located in the cell membrane and function as key cellular mechanotransducers for converting mechanical stimuli into electrochemical signals. Emerged as key molecular detectors of mechanical forces, Piezo channels' functions in bone have attracted more and more attention. Here, we summarize the current knowledge of Piezo channels and review the research advances of Piezo channels' function in bone by highlighting Piezo1's role in bone cells, including osteocyte, bone marrow mesenchymal stem cell (BM-MSC), osteoblast, osteoclast, and chondrocyte. Read More

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Antiepileptic Drug Tiagabine Does Not Directly Target Key Cardiac Ion Channels Kv11.1, Nav1.5 and Cav1.2.

Molecules 2021 Jun 9;26(12). Epub 2021 Jun 9.

Department of Organic Chemistry, Faculty of Pharmacy, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University in Toruń, 87-100 Toruń, Poland.

Tiagabine is an antiepileptic drug used for the treatment of partial seizures in humans. Recently, this drug has been found useful in several non-epileptic conditions, including anxiety, chronic pain and sleep disorders. Since tachycardia-an impairment of cardiac rhythm due to cardiac ion channel dysfunction-is one of the most commonly reported non-neurological adverse effects of this drug, in the present paper we have undertaken pharmacological and numerical studies to assess a potential cardiovascular risk associated with the use of tiagabine. Read More

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5-(Indol-2-yl)pyrazolo[3,4-]pyridines as a New Family of TASK-3 Channel Blockers: A Pharmacophore-Based Regioselective Synthesis.

Molecules 2021 Jun 25;26(13). Epub 2021 Jun 25.

Centro de Bioinformática, Simulación y Modelado (CBSM), Facultad de Ingeniería, Universidad de Talca, Poniente No. 1141, Talca 3460000, Chile.

TASK channels belong to the two-pore-domain potassium (K) channels subfamily. These channels modulate cellular excitability, input resistance, and response to synaptic stimulation. TASK-channel inhibition led to membrane depolarization. Read More

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Combination Therapy Using Sodium Zirconium Cyclosilicate and a Mineralocorticoid Receptor Antagonist in Patients with Heart Failure and Hyperkalemia.

Intern Med 2021 1;60(13):2093-2095. Epub 2021 Jul 1.

The Second Department of Internal Medicine, University of Toyama, Japan.

Hyperkalemia is a challenging comorbidity to manage in patients with heart failure and chronic kidney disease, particularly when administering renin-angiotensin-aldosterone system inhibitors. We encountered an 88-year-old woman with hypertensive heart failure and chronic kidney disease. A mineralocorticoid receptor antagonist was able to be safely administered despite persistent hyperkalemia when sodium zirconium cyclosilicate, a non-absorbed, non-polymer zirconium silicate compound that preferentially exchanges hydrogen and sodium for potassium and ammonium ions in the gastrointestinal tract, was concomitantly administered. Read More

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Gating mechanism and a modulatory niche of human GluN1-GluN2A NMDA receptors.

Neuron 2021 Jun 18. Epub 2021 Jun 18.

Institute of Neuroscience, State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai 200031, China; University of Chinese Academy of Sciences, Beijing 100049, China; Shanghai Center for Brain Science and Brain-Inspired Intelligence Technology, Shanghai 201210, China. Electronic address:

N-methyl-D-aspartate (NMDA) receptors are glutamate-gated calcium-permeable ion channels that are widely implicated in synaptic transmission and plasticity. Here, we report a gallery of cryo-electron microscopy (cryo-EM) structures of the human GluN1-GluN2A NMDA receptor at an overall resolution of 4 Å in complex with distinct ligands or modulators. In the full-length context of GluN1-GluN2A receptors, we visualize the competitive antagonists bound to the ligand-binding domains (LBDs) of GluN1 and GluN2A subunits, respectively. Read More

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A modified glass ionomer cement to mediate dentine repair.

Dent Mater 2021 08 24;37(8):1307-1315. Epub 2021 Jun 24.

Centre for Craniofacial and Regenerative Biology, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, UK; Otto Schott Institute of Materials Research, Faculty of Chemistry and Earth Sciences, Friedrich Schiller University Jena, Germany. Electronic address:

Objectives: Glass ionomer cements (GIC) can be used to protect dentine following caries removal. However, GIC have little biological activity on biological repair processes, which means that neo-dentine formation remains reliant on limited endogenous regenerative processes. Wnt/β-catenin signalling is known to play a central role in stimulating tertiary dentine formation following tooth damage and can be stimulated by a range of glycogen synthase kinase (GSK3) antagonists, including lithium ions. Read More

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Synthesis and evaluation of adenosine derivatives as A, A, A and A adenosine receptor ligands containing boron clusters as phenyl isosteres and selective A agonists.

Eur J Med Chem 2021 Jun 11;223:113607. Epub 2021 Jun 11.

Laboratory of Medicinal Chemistry, Institute of Medical Biology PAS, Lodowa 106, 92-232, Łódź, Poland. Electronic address:

A series of adenosine and 2'-deoxyadenosine pairs modified with a 1,12-dicarba-closo-dodecaborane cluster or alternatively with a phenyl group at the same position was synthesized, and their affinity was determined at A, A, A and A adenosine receptors (ARs). While AR affinity differences were noted, a general tendency to preferentially bind A AR over other ARs was observed for most tested ligands. In particular, 5'-ethylcarbamoyl-N-(3-phenylpropyl)adenosine (18), N-(3-phenylpropyl)-2-chloroadenosine (24) and N-(3-phenylpropyl)adenosine (40) showed nanomolar A affinity (K 4. Read More

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Programmed death-1 mediates venous neointimal hyperplasia in humans and rats.

Aging (Albany NY) 2021 06 24;13(12):16656-16666. Epub 2021 Jun 24.

School of Material Science and Engineering & Henan Key Laboratory of Advanced Magnesium Alloy & Key Laboratory of Materials Processing and Mold Technology, Ministry of Education, Zhengzhou University, Henan, China.

Venous neointimal hyperplasia can be a problem after vein interventions. We hypothesized that inhibiting programmed death-1 (PD-1) can decrease venous neointimal hyperplasia in a rat inferior vena cava (IVC) patch venoplasty model. The rats were divided into four groups: the control group was only decellularized without other special treatment; the PD-1 group was injected with a single dose of humanized PD-1 antibody (4 mg/kg); the PD-1 antibody coated patches group; the BMS-1 (a PD-1 small molecular inhibitor) coated patches group (PD-1 inhibitor-1). Read More

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Perturbation of astroglial Slc38 glutamine transporters by NH contributes to neurophysiologic manifestations in acute liver failure.

FASEB J 2021 07;35(7):e21588

Department of Molecular Medicine, University of Oslo (UiO), Oslo, Norway.

Ammonia is considered the main pathogenic toxin in hepatic encephalopathy (HE). However, the molecular mechanisms involved have been disputed. As altered glutamatergic and GABAergic neurotransmission has been reported in HE, we investigated whether four members of the solute carrier 38 (Slc38) family of amino acid transporters-involved in the replenishment of glutamate and GABA-contribute to ammonia neurotoxicity in HE. Read More

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The mineralocorticoid receptor leads to increased expression of EGFR and T-type calcium channels that support HL-1 cell hypertrophy.

Sci Rep 2021 Jun 24;11(1):13229. Epub 2021 Jun 24.

Julius Bernstein Institute of Physiology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 6, 06097, Halle, Saale, Germany.

The EGF receptor (EGFR) has been extensively studied in tumor biology and recently a role in cardiovascular pathophysiology was suggested. The mineralocorticoid receptor (MR) is an important effector of the renin-angiotensin-aldosterone-system and elicits pathophysiological effects in the cardiovascular system; however, the underlying molecular mechanisms are unclear. Our aim was to investigate the importance of EGFR for MR-mediated cardiovascular pathophysiology because MR is known to induce EGFR expression. Read More

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Self-assembly of an anion receptor with metal-dependent kinase inhibition and potent in vitro anti-cancer properties.

Nat Commun 2021 06 23;12(1):3898. Epub 2021 Jun 23.

School of Applied Sciences, University of Huddersfield Queensgate, Huddersfield, UK.

One topical area of supramolecular chemistry is the binding of anionic species but despite the importance of anions in diverse cellular processes and for cancer development, anion receptors or 'binders' have received little attention as potential anti-cancer therapeutics. Here we report self-assembling trimetallic cryptands (e.g. Read More

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Evaluation of efficiency and safety of combined montelukast sodium and budesonide in children with cough variant asthma: A protocol for systematic review and meta-analysis.

Medicine (Baltimore) 2021 Jun;100(25):e26416

Department of Pediatrics, the First People's Hospital of Jiangxia District.

Background: Cough variant asthma (CVA) is classified as a distinct form of asthma. As the primary or only symptom, cough is the leading cause for the most prevalent chronic cough among kids. The American College of Clinical Pharmacy, British Thoracic Society, and Chinese guidelines established for diagnosing and treating chronic cough in kids recommend inhaled corticosteroids, combined with leukotriene receptor antagonists when necessary. Read More

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Cryo-EM structure of SARS-CoV-2 ORF3a in lipid nanodiscs.

Nat Struct Mol Biol 2021 07 22;28(7):573-582. Epub 2021 Jun 22.

Department of Molecular & Cell Biology, University of California Berkeley, Berkeley, CA, USA.

SARS-CoV-2 ORF3a is a putative viral ion channel implicated in autophagy inhibition, inflammasome activation and apoptosis. 3a protein and anti-3a antibodies are found in infected patient tissues and plasma. Deletion of 3a in SARS-CoV-1 reduces viral titer and morbidity in mice, suggesting it could be an effective target for vaccines or therapeutics. Read More

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Oxaliplatin Depolarizes the IB4 Dorsal Root Ganglion Neurons to Drive the Development of Neuropathic Pain Through TRPM8 in Mice.

Front Mol Neurosci 2021 4;14:690858. Epub 2021 Jun 4.

Department of Pharmacology and Toxicology, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, IN, United States.

Use of chemotherapy drug oxaliplatin is associated with painful peripheral neuropathy that is exacerbated by cold. Remodeling of ion channels including TRP channels in dorsal root ganglion (DRG) neurons contribute to the sensory hypersensitivity following oxaliplatin treatment in animal models. However, it has not been studied if TRP channels and membrane depolarization of DRG neurons serve as the initial ionic/membrane drives (such as within an hour) that contribute to the development of oxaliplatin-induced neuropathic pain. Read More

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The anti-inflammatory effect of ε-viniferin by specifically targeting formyl peptide receptor 1 on human neutrophils.

Chem Biol Interact 2021 Aug 16;345:109490. Epub 2021 Jun 16.

Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Kwei-Shan, Taoyuan, 333, Taiwan, Republic of China; Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Kwei Shan, Taoyuan, 333, Taiwan, Republic of China; Molecular Medicine Research Center, Chang Gung University, Kwei Shan, Taoyuan, 333, Taiwan, Republic of China; Department of Laboratory Medicine, Chang Gung Memorial Hospital, Kwei Shan, Taoyuan, 333, Taiwan, Republic of China.

The uncontrol respiratory burst in neutrophils can lead to inflammation and tissue damage. This study investigates the effect and the underlying mechanism of ε-viniferin, a lignan from the root of Vitis thunbergii var. thunbergii, inhibits N-formyl-L-methionyl-L-leucyl-l-phenylalanine (fMLP) induced respiratory burst by antagonizing formyl peptide receptor 1 in human neutrophils. Read More

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[Ligands of the AMPA-subtype glutamate receptors: mechanisms of action and novel chemotypes].

Biomed Khim 2021 May;67(3):187-200

Lomonosov Moscow State University, Moscow, Russia.

Ionotropic glutamate receptors of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) subtype play a key role in synaptic plasticity representing one of the mechanisms for learning and memory formation. They can also serve as targets for the development of novel classes of pharmaceuticals for the treatment or substantive correction of many serious neurodegenerative and psychoneurological disorders. The search and studies of various types of AMPA receptor ligands attract considerable attention from academic organizations and pharmaceutical companies all over the world. Read More

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High-throughput screening of TRPV1 ligands in the light of the Bioluminescence Resonance Energy Transfer technique.

Mol Pharmacol 2021 Jun 14. Epub 2021 Jun 14.

IMS laboratory / CNRS UMR 5218, Bordeaux University, France

Ion channels are attractive drug targets for many therapeutic applications. However, high-throughput screening (HTS) of drug candidates is difficult and remains very expensive. We thus assessed the suitability of the Bioluminescence Resonance Energy Transfer (BRET) technique as a new HTS method for ion-channel studies by taking advantage of our recently characterized intra- and intermolecular BRET probes targeting the TRPV1 ion channel. Read More

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Punicalagin and zinc (II) ions inhibit the activity of SARS-CoV-2 3CL-protease in vitro.

Eur Rev Med Pharmacol Sci 2021 05;25(10):3908-3913

Faculty of Pharmacy, Middle East University, Amman, Jordan.

Objective: Coronavirus 2019 (COVID-19) has now been declared as a worldwide pandemic. Currently, no drugs have been endorsed for its treatment; in this manner, a pressing need has been developed for any antiviral drugs that will treat COVID-19. Coronaviruses require the SARS-CoV-2 3CL-Protease (3CL-protease) for cleavage of its polyprotein to yield a single useful protein and assume a basic role in the disease progression. Read More

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An essential role of the autophagy activating kinase ULK1 in snRNP biogenesis.

Nucleic Acids Res 2021 06;49(11):6437-6455

Institute of Molecular Medicine I, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.

The biogenesis of small uridine-rich nuclear ribonucleoproteins (UsnRNPs) depends on the methylation of Sm proteins catalyzed by the methylosome and the subsequent action of the SMN complex, which assembles the heptameric Sm protein ring onto small nuclear RNAs (snRNAs). In this sophisticated process, the methylosome subunit pICln (chloride conductance regulatory protein) is attributed to an exceptional key position as an 'assembly chaperone' by building up a stable precursor Sm protein ring structure. Here, we show that-apart from its autophagic role-the Ser/Thr kinase ULK1 (Uncoordinated [unc-51] Like Kinase 1) functions as a novel key regulator in UsnRNP biogenesis by phosphorylation of the C-terminus of pICln. Read More

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Unravelling the inhibitory zinc ion binding site and the metal exchange mechanism in human DPP III.

Phys Chem Chem Phys 2021 Jun;23(23):13267-13275

Ruđer Bošković Institute, Division of Organic Chemistry and Biochemistry, Croatia.

Dipeptidyl peptidase III (DPP III), a zinc-dependent exopeptidase, is widely distributed in organisms and present in almost all human tissues. In addition to its involvement in protein catabolism, it plays a role in oxidative stress and blood pressure regulation, and there is evidence of its involvement in pain modulation. Excess zinc ions have been found to inhibit its hydrolytic activity, but the binding affinity, binding site geometry, and mechanism of inhibitory activity have been unknown. Read More

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Retrograde nerve growth factor signaling modulates tooth mechanical hyperalgesia induced by orthodontic tooth movement via acid-sensing ion channel 3.

Int J Oral Sci 2021 06 4;13(1):18. Epub 2021 Jun 4.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Department of Orthodontics, West China Hospital of Stomatology, Sichuan University, Chengdu, China.

Orthodontic tooth movement elicits alveolar bone remodeling and orofacial pain that is manifested by tooth mechanical hyperalgesia. Nerve growth factor (NGF) is upregulated in periodontium and may modulate tooth mechanical hyperalgesia. The objectives were to examine the role of NGF in tooth mechanical hyperalgesia and to elucidate the underlying mechanisms. Read More

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Cationic Polyporphyrins as siRNA Delivery Vectors for Photodynamic and Gene Synergistic Anticancer Therapy.

ACS Appl Mater Interfaces 2021 Jun 4;13(23):27513-27521. Epub 2021 Jun 4.

State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, P. R. China.

Successful gene therapy is highly dependent on the efficiency of gene delivery, which is mostly achieved by the carrier. Current gene carriers are generally nontherapeutic and take over most of the proportion in the delivery systems. Therefore, a library of polymerized and cationic photosensitive drugs (polyphotosensitizers, pPSs) with HIF-1α siRNA delivery capability is constructed to realize using "drug" to deliver "gene". Read More

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Structure and Dynamics of Meprin β in Complex with a Hydroxamate-Based Inhibitor.

Int J Mol Sci 2021 May 26;22(11). Epub 2021 May 26.

Fraunhofer Institute for Cell Therapy and Immunology, Department of Drug Design and Target Validation, Weinbergweg 22, 06120 Halle (Saale), Germany.

The astacin protease Meprin β represents an emerging target for drug development due to its potential involvement in disorders such as acute and chronic kidney injury and fibrosis. Here, we elaborate on the structural basis of inhibition by a specific Meprin β inhibitor. Our analysis of the crystal structure suggests different binding modes of the inhibitor to the active site. Read More

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Structural Insights of Three 2,4-Disubstituted Dihydropyrimidine-5-carbonitriles as Potential Dihydrofolate Reductase Inhibitors.

Molecules 2021 May 29;26(11). Epub 2021 May 29.

Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt.

In this report, we describe the structural characterization of three 2,4-disubstituted-dihydropyrimidine-5-carbonitrile derivatives, namely 2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-4-propyl-1,6-dihydropyrimidine-5-carbonitrile , 4-(2-methylpropyl)-2-{[(4-nitrophenyl)methyl]sulfanyl}-6-oxo-1,6-dihydropyrimidine-5-carbonitrile , and 2-[(2-ethoxyethyl)sulfanyl]-6-oxo-4-phenyl-1,6-dihydropyrimidine-5-carbonitrile monohydrate . An X-ray diffraction analysis revealed that these compounds were crystallized in the centrosymmetric space groups and adopt an L-shaped conformation. One of the compounds () crystallized with a water molecule. Read More

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Gastric Serotonin Biosynthesis and Its Functional Role in L-Arginine-Induced Gastric Proton Secretion.

Int J Mol Sci 2021 May 30;22(11). Epub 2021 May 30.

Department of Physiological Chemistry, Faculty of Chemistry, University of Vienna, Althanstraße 14, 1090 Vienna, Austria.

Among mammals, serotonin is predominantly found in the gastrointestinal tract, where it has been shown to participate in pathway-regulating satiation. For the stomach, vascular serotonin release induced by gastric distension is thought to chiefly contribute to satiation after food intake. However, little information is available on the capability of gastric cells to synthesize, release and respond to serotonin by functional changes of mechanisms regulating gastric acid secretion. Read More

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