Research Interests: Biology, Medicine, Dopamine, Cell Differentiation, Humans, and 13 moreGlioma, Calcium channels, Polymerase Chain Reaction, dopamine receptor D4, Dopamine Receptors, Quinpirole, Neuroblastoma, Receptor, Gtp Binding Proteins, Brain Neoplasms, Calcium Channel Blockers, Sulpiride, and Pharmacology and pharmaceutical sciences
Research Interests: Chemistry, Pathogenesis, Calcium, Medicine, Multidisciplinary, and 15 moreNature, Macromolecular X-Ray Crystallography, Humans, Liver, Mice, Animals, Rational drug design, Pp, Carboxylic Acids, Protein Quaternary Structure, Protein Binding, Amyloidosis, Dimerization, plasma proteins, and Minimum Inhibitory Concentration
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It has been suggested that one of the effects of glycine at the N-methyl-D-aspartate (NMDA) receptor complex is to reduce the amount of apparent receptor desensitization. Thus, blockade with a glycine site antagonist results in NMDA... more
It has been suggested that one of the effects of glycine at the N-methyl-D-aspartate (NMDA) receptor complex is to reduce the amount of apparent receptor desensitization. Thus, blockade with a glycine site antagonist results in NMDA responses that show an increased amount of fade. In agreement with this, we found that antagonism of NMDA-evoked whole-cell currents by 7-chlorokynurenic acid (7-Cl-KYNA) indeed resulted in NMDA responses that displayed an increased amount of fade. However, those responses that were antagonized by (+)-HA-966 showed the opposite, i.e., less tendency to fade. On examination of these responses, it appeared that those produced in the presence of (+)-HA-966 were slower in onset and faster in offset than control responses recorded in the presence of glycine alone. Kinetic analysis of the on- and off-rates of NMDA- and glutamate-evoked NMDA receptor-mediated responses revealed that these were markedly affected by (+)-HA-966 but only slightly by 7-Cl-KYNA. The d...
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The Bradykinin B1 and B2 receptors are GPCRs that play a role in pain and inflammation. The B2 receptor is constitutively expressed under normal physiological conditions and its activation in response to inflammatory or noxious insult is... more
The Bradykinin B1 and B2 receptors are GPCRs that play a role in pain and inflammation. The B2 receptor is constitutively expressed under normal physiological conditions and its activation in response to inflammatory or noxious insult is believed to account for acute pain
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The accumulation of β-amyloid peptides (Aβ) into senile plaques is one of the hallmarks of Alzheimer disease. Aggregated Aβ is toxic to cells in culture and this has been considered to be the cause of neurodegeneration that occurs in the... more
The accumulation of β-amyloid peptides (Aβ) into senile plaques is one of the hallmarks of Alzheimer disease. Aggregated Aβ is toxic to cells in culture and this has been considered to be the cause of neurodegeneration that occurs in the Alzheimer disease brain. The discovery of compounds that prevent Aβ toxicity may lead to a better understanding of the processes involved and ultimately to possible therapeutic drugs. Low nanomolar concentrations of Aβ1-42 and the toxic fragment Aβ25-35 have been demonstrated to render cells more sensitive to subsequent insults as manifested by an increased sensitivity to formazan crystals following MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) reduction. Formation of the toxic β-sheet conformation by Aβ peptides is increased by negatively charged membranes. Here we demonstrate that phloretin and exifone, dipolar compounds that decrease the effective negative charge of membranes, prevent association of Aβ1-40 and Aβ25-35 to nega...
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Research Interests: Chemistry, Organic Chemistry, Medicinal Chemistry, Mass Spectrometry, Magnetic Resonance Spectroscopy, and 15 moreMedicine, Brain, Mice, Animals, Quinolones, Antagonist, Hydrogen Bond, In Vivo, Medicinal, Glycine, Methyl Group, Potency, Molecular Structure, binding sites, and Pharmacology and pharmaceutical sciences
3 R-(+)- cis-4-Methyl-HA966 (L-687,414) is a novel and selective, low intrinsic activity, partial agonist at the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Thus, while it acts primarily to block NMDA receptor function in... more
3 R-(+)- cis-4-Methyl-HA966 (L-687,414) is a novel and selective, low intrinsic activity, partial agonist at the glycine site of the N-methyl-d-aspartate (NMDA) receptor. Thus, while it acts primarily to block NMDA receptor function in the presence of glycine, it fails to produce a complete block of NMDA receptor activation. In this study, we have investigated its neuroprotective effects in a rat model of focal ischaemia, involving permanent occlusion of the left middle cerebral artery. L-687,414 was administered as a bolus dose of 17.6 mg/kg i.v. straight after the occlusion or as a bolus dose + infusion for 4 h. The doses of L-687,414 used for the infusion studies were 7 mg/kg i.v. +7 mg/kg/h, 14 mg/kg + 14 mg/kg/h, or 30 mg/kg + 30 mg/kg/h. The 17.6-mg/kg dose gave an estimated peak plasma level of 24 μg/ml, which decayed with a tI/2 of 56 min. The three infusion dosing regimens gave mean plasma levels over the 4 h of 11, 25, and 61 μg/ml plasma, respectively. The 17.6-mg/kg dose...
Research Interests: Chemistry, Medicine, Neuroprotection, Glutamate, Caudate Nucleus, and 15 moreCerebral Cortex, Animals, Male, Brain Ischemia, Antagonist, Clinical Sciences, Neurosciences, Brain Damage, Middle Cerebral Artery, Control Group, Neuroprotective Agents, Agonist, NMDA receptor, Adverse effect, and Cardiovascular medicine and haematology
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The antagonist effect of (+/-)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers... more
The antagonist effect of (+/-)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of (+/-)-HA-966 were resolved, the (R)-(+)-enantiomer was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [3H]glycine binding to rat cerebral cortex synaptic membranes with an IC50 of 12.5 microM, whereas (-)-HA-966 had an IC50 value of 339 microM. In electrophysiological experiments, (+)-HA-966 selectively antagonized NMDA receptor responses in rat cortical slices, whereas the (-)-enantiomer was much weaker. On cultured cor...
Research Interests: Chemistry, Kinetics, Autonomic Nervous System, Dopamine, Cerebral Cortex, and 15 moreAnimals, Male, Central Nervous System, Antagonist, Chemical Reaction, Body Weight, Glycine, Furans, Butyrolactone, Agonist, Isomerism, Acoustic Stimulation, Corpus striatum, Cortical neurons, and In Vitro Techniques
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Glycine markedly potentiates N-methyl-D-aspartate (N-Me-D-Asp) responses in mammalian neurons by an action at a modulatory site on the N-Me-D-Asp receptor-ionophore complex. Here we present evidence that 7-chlorokynurenic acid (7-Cl KYNA)... more
Glycine markedly potentiates N-methyl-D-aspartate (N-Me-D-Asp) responses in mammalian neurons by an action at a modulatory site on the N-Me-D-Asp receptor-ionophore complex. Here we present evidence that 7-chlorokynurenic acid (7-Cl KYNA) inhibits N-Me-D-Asp responses by a selective antagonism of glycine at this modulatory site. In rat cortical slices 7-Cl KYNA (10-100 microM) noncompetitively inhibited N-Me-D-Asp responses, and this effect could be reversed by the addition of glycine (100 microM) or D-serine (100 microM). Radioligand binding experiments showed that 7-Cl KYNA had a much higher affinity for the strychnine-insensitive [3H]glycine binding site (IC50 = 0.56 microM) than for the N-Me-D-Asp (IC50 169 microM), quisqualate (IC50 = 153 microM), or kainate (IC50 greater than 1000 microM) recognition sites. In whole-cell patch-clamp recordings from rat cortical neurones in culture, the inhibitory effects of 7-Cl KYNA on N-Me-D-Asp-induced currents could not be overcome by incr...
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3-Amino-1-hydroxypyrrolid-2-one (HA-966) has been known for several years as an excitatory amino acid antagonist, acting principally at the N-methyl-D-aspartate (NMDA) receptor subtype. We report here that HA- 966 blocks NMDA responses... more
3-Amino-1-hydroxypyrrolid-2-one (HA-966) has been known for several years as an excitatory amino acid antagonist, acting principally at the N-methyl-D-aspartate (NMDA) receptor subtype. We report here that HA- 966 blocks NMDA responses through a selective interaction with the glycine modulatory site present within the receptor complex. In radioligand binding experiments, HA-966 inhibited strychnine- insensitive 3H-glycine binding to rat cerebral cortex synaptic plasma membranes with an IC50 of 17.5 microM. At concentrations up to 1 mM, HA- 966 caused minimal inhibition of radioligand binding to the transmitter recognition sites of the NMDA, quisqualate, or kainate receptor subtypes and was similarly inactive against the binding of 3H- strychnine to rat spinal cord/brain stem membranes. In electrophysiological experiments, HA-966 produced a selective block of NMDA responses in a rat cortical slice preparation. The degree of antagonism caused by HA-966 was maximal at 250 microM and wa...
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Research Interests: Neuroscience, Animal Behavior, Long Term Potentiation, Calcium, In Situ Hybridization, and 15 moreHippocampus, Glutamate, Cerebral Cortex, Mice, Animals, Gene Targeting, Autoradiography, Seizures, Homologous Recombination, Glycine, Binding Site, NMDA receptor, Psychology and Cognitive Sciences, reverse transcriptase polymerase chain reaction, and Medical and Health Sciences
Research Interests: Genetics, Animal Behavior, Long Term Potentiation, Hippocampus, Mice, and 15 moreAnimals, Drug Resistance, Gene Targeting, Hyperkinesis, Glycine, Biogenic amines, Binding Site, Glutamic Acid, Morris water maze, Excitatory Postsynaptic Potentials, Corpus striatum, Antipsychotic agents, binding sites, Medical and Health Sciences, and In Vitro Techniques
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Research Interests: Neuroscience, Membrane Proteins, Medicine, Hippocampus, Brain, and 15 moreHumans, Mutation, Mice, Animals, Male, Neuronal Plasticity, Age Factors, Disease Progression, Brain Chemistry, Cross Sectional Studies, Maze Learning, Amyloidosis, Cognition disorders, Medical and Health Sciences, and In Vitro Techniques
The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease... more
The tau spreading hypothesis provides rationale for passive immunization with an anti-tau monoclonal antibody to block seeding by extracellular tau aggregates as a disease-modifying strategy for the treatment of Alzheimer's disease (AD) and potentially other tauopathies. As the biochemical and biophysical properties of the tau species responsible for the spatio-temporal sequences of seeding events are poorly defined, it is not yet clear which epitope is preferred for obtaining optimal therapeutic efficacy. Our internal tau antibody collection has been generated by immunizations with different tau species: aggregated- and non-aggregated tau and human postmortem AD brain-derived tau fibrils. In this communication, we describe and characterize a set of these anti-tau antibodies for their biochemical and biophysical properties, including binding, tissue staining by immunohistochemistry, and epitope. The antibodies bound to different domains of the tau protein and some were demonstra...
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Research Interests: Neuroscience, Psychology, Cognitive Science, Aging, Biology, and 15 moreMedicine, Transgenic Mice, Signal Transduction, Hippocampus, Humans, Mutation, Mice, Animals, SYNAPSES, Presenilin-2, Alzheimer Disease, Neurosciences, Amyloid Beta Precursor Protein, In Vitro Techniques, and Electric stimulation
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Since the mid 1980s, there has been a great deal of enthusiasm within both academia and industry about the therapeutic potential of drugs targeting the NMDA subtype of glutamate receptors. That early promise is just beginning to translate... more
Since the mid 1980s, there has been a great deal of enthusiasm within both academia and industry about the therapeutic potential of drugs targeting the NMDA subtype of glutamate receptors. That early promise is just beginning to translate into approvable drugs. Here we review the reasons for this slow progress and critically assess the future prospects for drugs that act on NMDA receptor pathways, including potential treatments for some major disorders such as stroke and Alzheimer's disease, for which effective therapies are still lacking.
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The mammalian N-methyl-D-aspartate (NMDA) receptor complex is though to consist of an NR1 subunit in combination with one or more of the four NR2 subunits (A, B, C, and D). When corresponding cDNAs are expressed in Xenopus oocytes, ion... more
The mammalian N-methyl-D-aspartate (NMDA) receptor complex is though to consist of an NR1 subunit in combination with one or more of the four NR2 subunits (A, B, C, and D). When corresponding cDNAs are expressed in Xenopus oocytes, ion channels with the characteristic profile of NMDA receptors are formed. The receptor is unique in requiring two coagonists, glutamate and glycine, for activation of the channel. We have used site-directed mutagenesis to study amino acids in the human NR1 subunit that contribute to the glycine binding site of the NMDA receptor without affecting the agonist site for glutamate. Mutations to D481 and K483 produced receptors with up to 160-fold lower affinities for glycine, as well as other agonists and partial agonists, without affecting maximum current size or the degree of agonist efficacy. The D481A mutation also led to 40-50-fold lower affinities for two structurally diverse glycine site antagonists. From these data we propose that the carboxyl group o...
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The N-methyl-D-aspartate (NMDA) receptor is unique among the ligand-gated ion channels, in that the gating process requires the binding of two independent coagonists, glutamate and glycine. Receptor binding experiments have suggested that... more
The N-methyl-D-aspartate (NMDA) receptor is unique among the ligand-gated ion channels, in that the gating process requires the binding of two independent coagonists, glutamate and glycine. Receptor binding experiments have suggested that the coagonist recognition sites interact with one another in an allosteric manner, and previous work in this laboratory has provided additional functional support in favor of an allosteric coupling; the affinity of glutamate for its recognition site was reduced when a partial agonist, (+)-HA-966, occupied the glycine site, compared with the affinity when glycine itself was bound to the receptor. The present experiments have taken these observations a step further and compare the effects of several glycine site ligands with different affinities and intrinsic activities (determined from equilibrium concentration-response curves) on glutamate off-rate. Thus, the dissociation rate for the decay of glutamate-activated membrane currents in voltage-clampe...
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The G-protein coupled metabotropic glutamate receptor mGlu5 plays a pivotal role as a modulator of synaptic plasticity, ion channel activity and excitotoxicity. Two splice variants, hmGlu5a and -5b have been reported previously. During... more
The G-protein coupled metabotropic glutamate receptor mGlu5 plays a pivotal role as a modulator of synaptic plasticity, ion channel activity and excitotoxicity. Two splice variants, hmGlu5a and -5b have been reported previously. During screening of a human brain cDNA library for hmGlu5a, we identified a novel variant (hmGlu5d) generated by alternative splicing at the C-terminal domain. The predicted hmGlu5d protein
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Research Interests: Neurobiology Of Disease, Biology, Medicine, Transgenic Mice, Hippocampus, and 14 moreHumans, Mutation, Mice, Animals, Tauopathies, Clinical Sciences, Analysis of Variance, Age Factors, Disease Progression, Neurofibrillary Tangles, Neurosciences, Gene Expression Regulation, Functional Laterality, and Tau proteins
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Non-competitive antagonists have become important tools for investigating the basic mechanisms of NMDA receptor function. Such compounds (eg MK-801, PCP) are thought to act at the level of the NMDA receptor-associated ion channel and many... more
Non-competitive antagonists have become important tools for investigating the basic mechanisms of NMDA receptor function. Such compounds (eg MK-801, PCP) are thought to act at the level of the NMDA receptor-associated ion channel and many show a marked ...