A5088259448- Neuroscience and Neuropharmacology Research
- Receptor Mechanisms and Signaling
- Molecular Sensors and Ion Detection
- Chemical Synthesis and Analysis
- Ion channel regulation and function
- Nicotinic Acetylcholine Receptors Study
- Bioactive Compounds and Antitumor Agents
- Phenothiazines and Benzothiazines Synthesis and Activities
- Neuropeptides and Animal Physiology
- Synthesis and Biological Evaluation
- Amino Acid Enzymes and Metabolism
- Stress Responses and Cortisol
- X-ray Diffraction in Crystallography
- Biochemical Analysis and Sensing Techniques
- Crystallization and Solubility Studies
- Circadian rhythm and melatonin
- Crystallography and molecular interactions
- Pharmacological Receptor Mechanisms and Effects
- Neurotransmitter Receptor Influence on Behavior
- Synthesis and biological activity
- Treatment of Major Depression
- Neurobiology and Insect Physiology Research
- Pain Mechanisms and Treatments
- Synthesis of heterocyclic compounds
- Analytical Chemistry and Chromatography
University of Copenhagen
2015-2024
American Pharmacists Association
2010
Lundbeck (Denmark)
2005-2008
University of Siena
2001-2008
Tel Aviv University
2002
University of Toronto
1993-1995
McMaster University
1987-1992
McMaster University Medical Centre
1985-1989
Health Sciences Centre
1985
University of Oxford
1977
The orphan glutamate-like receptor GluRδ2 is predominantly expressed in Purkinje cells of the central nervous system. classification to ionotropic glutamate family based on sequence similarities, because does not form functional homomeric glutamate-gated ion channels transfected cells. Studies −/− knockout mice as well with naturally occurring mutations gene have demonstrated an essential role cerebellar long-term depression, motor learning, coordination, and synaptogenesis. However, lack a...
A comparison of the pharmacological and physiological properties metabotropic glutamate 1 alpha beta receptors (mGluR1 mGluR1 beta) expressed in baby hamster kidney (BHK 570) cells was performed. The receptor is an alternatively spliced form with a modified carboxy terminus. Immunoblots membranes from two cell lines probed receptor-specific antipeptide antibodies showed that migrated M(r) = 154,000, whereas 96,000. Immunofluorescence imaging BHK 570 revealed localized to patches along...
The G-protein-coupled metabotropic glutamate receptor mGluR1 alpha and the ionotropic GluR6 were examined for posttranslational palmitoylation. Recombinant receptors expressed in baculovirus-infected insect cells or human embryonic kidney metabolically labeled with [3H]palmitic acid. was not whereas kainate after incubation [3H]palmitate. [3H]palmitate labeling of eliminated by treatment hydroxylamine, indicating that due to palmitoylation at a cysteine residue via thioester bond....
The inhibitory effect of 3-hydroxy-4-amino-4,5,6,7-tetrahydro-1,2-benzisoxazole (<i>exo</i>-THPO) and its <i>N</i>-methylated (<i>N</i>-methyl-<i>exo</i>-THPO) and<i>N</i>-ethylated (<i>N</i>-ethyl-<i>exo</i>-THPO) analogs, derived from γ-aminobutyric acid (GABA) 4,5,6,7-tetrahydroisoxazolo[4,5-<i>c</i>]pyridin-3-ol (THPO) on GABA transport was investigated using cultured neocortical neurons (GABA-ergic) astrocytes cloned mouse transporters GAT1–4 expressed in human embryonic kidney (HEK)...
The prevailing structural model for ligand activation of ionotropic glutamate receptors posits that agonist efficacy arises from the stability and magnitude induced domain closure in ligand-binding core structure. Here we describe an exception to correlation between closure. A weakly efficacious partial very low potency homomeric iGluR5 kainate receptors, 8,9-dideoxyneodysiherbaine (MSVIII-19), a fully closed core. degree relative closure, ∼30°, was similar resolved with structurally related...
More than 50 structures have been reported on the ligand-binding core of ionotropic glutamate receptor iGluR2 that belongs to 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid-type receptors. In contrast, kainic iGluR5 has only crystallized with three different ligands. Hence, additional are needed broaden understanding properties iGluR5, and conformational changes leading channel opening closing. Here, we present two iGluR5; one as a complex partial agonist...
In the mammalian central nervous system, (S)-glutamate (Glu) is released from presynaptic neuron where it activates a plethora of pre- and postsynaptic Glu receptors. The fast acting ionotropic receptors (iGluRs) are ligand gated ion channels believed to be involved in vast number neurological functions such as memory learning, synaptic plasticity, motor function. synthesis 14 enantiopure 2,4-syn-Glu analogues 2b–p accessed by short efficient chemoenzymatic approach starting readily...
We have recently reported that by converting a perforin inhibitor into an l-type amino acid transporter 1 (LAT1)-utilizing prodrug its cellular uptake can be greatly increased. The aim of the present study was to determine in vivo and brain pharmacokinetics two inhibitors their LAT1-utilizing prodrugs 2. In addition, mechanism entry primary mouse cortical neurons astrocytes were evaluated. After 23 μmol/kg i.p. bolus injection, prodrugs' unbound area under concentration curve 0.3 nmol/g ×...
Significance α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the main excitatory in brain. Although neurotransmitter binding to AMPARs is well understood, knowledge regarding their activation mechanisms remains incomplete. We exploited genetic insertion of fluorescent proteins create displaying fluorescence resonance energy transfer and allow optical monitoring conformational changes receptor. Ligand-driven observed occur two intracellular domains receptor that...
(S)-Glutamic acid (Glu) is the major excitatory neurotransmitter in central nervous system (CNS) activating plethora of ionotropic Glu receptors (iGluRs) and metabotropic (mGluRs). In this paper, we present a chemo-enzymatic strategy for enantioselective synthesis five new analogues 2a−f (2d exempt) holding functionalized substituent 4-position. Nine 2a−j are characterized pharmacologically at native 2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic (AMPA), kainic (KA),...
The most common solid tumors show intrinsic multidrug resistance (MDR) or inevitably acquire such when treated with anticancer drugs. In this work, we describe the discovery of a peripherally restricted, potent, competitive NMDA receptor antagonist 1l by structure–activity study broad-acting ionotropic glutamate 1a. Subsequently, demonstrate that augments cytotoxic action sorafenib in murine hepatocellular carcinoma cells. underlying biological mechanism was shown to be interference lipid...
Although GluR1 o and GluR3 are homologous at the amino acid level, desensitizes approximately threefold faster than . By creating chimeras of point exchanges in their S2 regions, two residues were identified to be critical for desensitization: Y716 R/G RNA-edited site, R757. With creation double-point mutant (Y716F, R757G)GluR1 , complete exchange desensitization rate that was obtained. In addition, both potency affinity subtype-selective agonist bromohomoibotenic exchanged by Y716F...
Ionotropic glutamate receptors mediate most rapid excitatory synaptic transmission in the mammalian central nervous system, and their involvement neurological diseases has stimulated widespread interest structure function. Despite a large number of agonists developed so far, few display selectivity among (<i>S</i>)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propionic acid (AMPA)-receptor subtypes. The present study provides X-ray structures receptor 2 (GluR2)-selective partial agonist...