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Haruhiko Shinozaki - One of the best experts on this subject based on the ideXlab platform.
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Selective metabotropic receptor agonists distinguish non-ionotropic glutamate binding sites.
Brain Research, 1997Co-Authors: Claudia M. Testa, Haruhiko Shinozaki, Zane R. Hollingsworth, John B. Penney, Anne B. YoungAbstract:Abstract Metabotropic glutamate receptors (mGluRs) are thought to mediate diverse processes in brain including synaptic plasticity and excitotoxicity. These receptors are often divided into three groups by their pharmacological profiles. [3H]Glutamate binding in the presence of compounds selective for ionotropic glutamate receptors can be used as a general assay for these receptors; subtypes of this non-ionotropic [3H]glutamate binding differ in both pharmacology and anatomical distribution, and are differentially sensitive to quisqualate. The characteristics of these binding sites are consistent with those of group 1 (high-affinity quisqualate) and group 2 (low-affinity quisqualate) mGluRs. Under our assay conditions, no [3H]glutamate binding to group 3-like ( l -AP4 sensitive) sites could be demonstrated. We have attempted to characterize particular agents which may selectively measure [3H]glutamate binding to mGluR subtypes. We used two isomers of 2-(carboxycyclopropyl)glycine, l -CCG-I and l -CCG-II, and the (2S,1′R,2′R,3′R) isomer of 2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) as competitors of non-ionotropic [3H]glutamate binding sites. DCG-IV clearly distinguishes two binding sites. Quantitative levels of DCG-IV binding by anatomic region correlate with quisqualate-defined binding subtypes: high-affinity DCG-IV binding correlates with low-affinity quisqualate binding, whereas low-affinity DCG-IV binding correlates with high-affinity quisqualate binding. l -CCG-II displaces only one type of non-ionotropic [3H]glutamate binding, corresponding to high-affinity quisqualate binding. Therefore DCG-IV and l -CCG-II at appropriate concentrations appear to distinguish binding to putative group 2 vs. group 1 mGluRs. l -CCG-I displaces both high- and low-affinity quisqualate binding sites, but unlike the other two compounds, does not clearly distinguish between them.
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(2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl) glycine positively modulates metabotropic glutamate receptors coupled to polyphosphoinositide hydrolysis in rat hippocampal slices.
Brain Research, 1994Co-Authors: Armando A. Genazzani, Haruhiko Shinozaki, M.r. L'episcopo, G. Casabona, Ferdinando NicolettiAbstract:In rat hippocampal slices, the novel metabotropic glutamate receptor (mGluR) ligand, (1S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) enhanced the stimulation of polyphosphoinositide (PPI) hydrolysis elicited by quisqualate or by submaximal concentrations of ibotenate or (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD). The enhancing effect of DCG-IV was (i) specific for mGluR agonists, (ii) restricted to hippocampal slice preparation, (iii) reversible, and (iv) not subject to homologous desensitization, in addition, DCG-IV did not interact with L-2-amino-4-phosphonobutanoate (AP4), a noncompetitive antagonist of mGluRs coupled to PPI hydrolysis in brain slices [32]. The action of DCG-IV on quisqualate-stimulated PPI hydrolysis was insensitive to antagonists of ionotropic glutamate receptors and did not appear to be a consequence of a reduction in the intracellular levels of cAMP [14]. When the stimulation of PPI hydrolysis was measured as a function of the incubation time, DCG-IV potentiated quisqualate-stimulated PPI hydrolysis after 60 min of incubation, when quisqualate had already reached its maximal effect. Knowing that activation of protein kinase C (PKC) limits the extent of mGluR agonist-stimulated PPI hydrolysis over time, we have studied the enhancing effect of DCG-IV in the presence of the PKC activator, 12-O-tetradecanoylphorbol-13-acetate (TPA). As expected [9], TPA reduced quisqualate-stimulated PPI hydrolysis in control slices, but was inactive in slices incubated in the presence of DCG-IV. Taken collectively, these results suggest that DCG-IV positively modulates the activity of mGluRs coupled to PPI hydrolysis through a mechanism, which involves PKC-mediated phosphorylation processes.
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Metabotropic glutamate receptor agonist DCG-IV as NMDA receptor agonist in immature rat hippocampal neurons
European journal of pharmacology, 1994Co-Authors: V W Wilsch, Haruhiko Shinozaki, Vladimir I. Pidoplichko, Thoralf Opitz, Klaus G. ReymannAbstract:The electrophysiological action of (2S,1′R;2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV) on the NMDA receptor was investigated with the help of concentration-jump experiments on freshly dissciated hippocampal CA1 and CA3 neurons of rats. Inward currents elicited by a pulse of DCG-IV were insensitive to 6-cyano-7-nitroquinozaline-2,3-dione (CNQX) and could be blocked by D-(−)-2-amino-5-phosphonopentanoic acid (D-AP5) and magnesium and enhanced by glycine. The substance displayed cross-desensitization with NMDA but not with kainate or (RS)-α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA). Dose-response curves showed that DCG-IV was weaker than NMDA but more potent than glutamate in eliciting agonist-gated currents. From these data we conclude that DCG-IV has to be used with caution as a tool for the investigation of metabotropic glutamate receptors.
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Agonists for metabotropic glutamate receptors in the rat delay recovery from halothane anesthesia.
European journal of pharmacology, 1994Co-Authors: Masashi Miyamoto, Michiko Ishida, Shin Kwak, Haruhiko ShinozakiAbstract:Abstract Intraventricular injection of (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), a potent agonist for metabotropic glutamate receptors, to rats retarded dose-dependently the recovery from halothane anesthesia at a dose range from 30 to 300 pmol/rat. At a dose of 300 pmol/rat, recovery was prolonged up to about 630% of the control. (2S,1′S,2′S)-2-(carboxycycloprophyl)glycine (L-CCG-I) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid ((1S,3R)-ACPD) also delayed recovery, but doses much higher than those of DCG-IV were required (about 300 and 1000 times, respectively). These results suggest that some agonists for a certain kind of metabotropic glutamate receptors have a central depressant action in the rat.
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Interaction between metabotropic receptors and purinergic transmission in rat hippocampal slices.
Brain research, 1994Co-Authors: G. Casabona, Haruhiko Shinozaki, M.r. L'episcopo, Ferdinando Nicoletti, P. Di Iorio, R. Ciccarelli, E. De Bernardis, Francesco CaciagliAbstract:Abstract Inhibition of forskolin-stimulated cAMP formation by (1S,3R)-1-aminocyclopentane-1,3-dicar☐ylic acid (ACDP) in rat hippocampal slices was partially obliterated by the adenosine-depleting enzyme, adenosine deaminase, or by the adenosine receptor agonist, 5′-(N-ehtylcar☐amido)-adenosine, suggesting that activation of metabotropic glutamate receptors (mGluRs) modulates the release of endogenous adenosine. Consistent with this hypothesis, forskolin stimulated the release of purines from rat hippocampal slices, and this effect was reduced by 1S,3R-ACPD. To establish which transduction pathway is involved in the modulation of forskolin-stimulated purine release, we have tested the novel mGluR2 agonist, (2S,1′R,2′R,3′R)-2-(2,3-dicar☐ycyclopropyl)glycine (DCG-IV), which reduced forskolin-stimulated cAMP formation but, as opposed to 1S,3R-ACDP, did not stimulated polyphosphoinositide hydrolysis. DCG-IV was highly potent and more efficacious than 1S,3R-ACDP in inhibiting forskolin-stimulated purine release. Neither DCG-IV nor 1S,3R-ACDP reduced the release of purines stimulated by depolarizing concentrations of K+, suggesting that their effect was stimulus-specific. These results indicate that, in rat hippocampal slices, activation of mGluR2 receptors attenuates the release of purines induced by forskolin, a process that amplifies the final effect of forskolin on cAMP formation as a result of A2 purinergic receptor activation. Thus, the final effect of mGluR agonists on forskolin-stimulated cAMP formation in hippocampal slices depends on both a direct inhibition of adenyl cyclase and the inhibition of adenosine release.
H. Shinozaki - One of the best experts on this subject based on the ideXlab platform.
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DCG-IV, a potent metabotropic glutamate receptor agonist, as an NMDA receptor agonist in the rat cortical slice
Brain Research, 1997Co-Authors: Yoshiaki Uyama, Michiko Ishida, H. ShinozakiAbstract:The depolarization induced by DCG-IV, a potent agonist for Group II metabotropic glutamate receptors (Group II mGluRs), was depressed by selective antagonists for NMDA receptors in the rat cortical slice, but was not affected even by a high concentration of a selective antagonist for Group II mGluRs. DCG-IV caused depolarization more effective than NMDA in a dose-dependent manner with a threshold concentration of 3 microM in rat cortical slices, while DCG-IV was less active than NMDA in rat spinal cords. These actions should be carefully considered particularly when DCG-IV is used as an agonist for mGluRs in vivo.
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ANTICONVULSIVE AND NEUROPROTECTIVE ACTIONS OF A POTENT AGONIST (DCG-IV) FOR GROUP II METABOTROPIC GLUTAMATE RECEPTORS AGAINST INTRAVENTRICULAR KAINATE IN THE RAT
Neuroscience, 1997Co-Authors: M. Miyamoto, M. Ishida, H. ShinozakiAbstract:Anticonvulsive and neuroprotective effects of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl) glycine (DCG-IV), a potent agonist for Group II metabotropic glutamate receptors, were examined in vivo against the excitotoxicity of kainic acid in the rat. Intraventricular injection of kainic acid (2 nmol) induced circling behavior and wet-dog shakes soon after injection, followed by episodes of limbic motor seizures at intervals of several minutes (sporadic limbic motor seizures). The frequency of sporadic limbic motor seizures gradually increased until seizures occurred incessantly (continuous limbic motor seizures). Intraventricular kainic acid also caused severe selective neuron damage in the hippocampal CA3 region, limbic lobe and medial geniculate body. Prolonged intraventricular infusion of DCG-IV (24-240 pmol/h) for 17 h before and 7 h after the application of kainic acid decreased the incidence of the continuous limbic motor seizures and the degree of neuronal damage in circumscribed brain areas. However, the behavioral changes observed immediately after the administration of kainic acid were unaffected by prolonged intraventricular infusion with DCG-IV (8-2400 pmol/h). Similarly, the occurrence of sporadic limbic motor seizures was only slightly reduced by the administration of DCG-IV (8-800 pmol/h). High doses of DCG-IV, greater than 800 pmol/h, afforded no protection against kainate-induced lesions; rather, the degradation of hippocampal CA1 pyramidal neurons was increased under such conditions. Single injections of DCG-IV (10-300 pmol/rat) in the lateral ventricle did not affect kainate neurotoxicity. Thus, prolonged infusion of DCG-IV showed a bell-shaped doso-response relationship with regard to protection against kainate-induced neurotoxicity.
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Neurotoxicity of (2S,1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)glycine, a potent agonist for class II metabotropic glutamate receptors, in the rat
Neuroscience, 1996Co-Authors: S. Kwak, M. Miyamoto, M. Ishida, H. ShinozakiAbstract:Abstract Neurotoxicity of (2S,1'R,2'R,3'R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), a potent agonist for metabotropic glutamate receptors negatively coupled to adenylyl cyclase, was investigated in vivo by the intraventricular administration in the rat, compared with that of (2S,1′S,2′S)-2-(carboxy-cyclopropyl)glycine (L-CCG-I) and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid [(1S,3R)-ACPD]. Neither L-CCG-I nor (1S,3R)-ACPD caused any apparent pathological change in the brain at an intraventricular dose of 1 μmol, whereas DCG-IV induced selective neuronal damage in some rats at higher doses than 3 nmol. The neurotoxicity was intensified in a dose-dependent manner, and at a dose of 50 nmol DCG-IV caused repetitive seizures and selective neuronal damage in all cases. Neuronal damage was pronounced in the cingulate cortex, lateral septum and hippocampus, and a few degenerating neurons were observed also in other brain areas, such as the striatum, thalamus or neocortex. Since DCG-IV activates N -methyl- d -aspartate-type receptors as well at relatively high concentrations, the protective effect of a competitive antagonist for N -methyl- d -aspartate receptors, 3-[(RS)-2-carboxypiperazin-4-yl]propyl-1-phosphonic acid (CPP), was examined on the neurotoxicity of DCG-IV. Although a combined treatment with CPP (0.1 nmol) completely blocked the neurotoxicity of N -methyl- d -aspartate (100 nmol), at least 3 nmol of CPP was necessary to decrease the neurotoxicity of DCG-IV (50 nmol) to a considerable extent. The synergistic activation of metabotropic glutamate receptors and N -methyl- d -aspartate receptors is suggested as a possible mechanism underlying the selective neuronal damage induced by DCG-IV, although a direct participation of metabotropic glutamate receptors in glutamate neurotoxicity is not deniable.
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Activation of Class II or III Metabotropic Glutamate Receptors Protects Cultured Cortical Neurons Against Excitotoxic Degeneration
The European journal of neuroscience, 1995Co-Authors: Valeria Bruno, Agata Copani, Giuseppe Battaglia, R Raffaele, H. Shinozaki, Rona G. Giffard, G. Raciti, Ferdinando NicolettiAbstract:Trans-1-aminocyclopentane-1,3-dicarboxylic acid, a mixed agonist of all metabotropic glutamate receptor (mGluR) subtypes, is known to produce either neurotoxic or neuroprotective effects. We have therefore hypothesized that individual mGluR subtypes differentially affect neurodegenerative processes. Selective agonists of subtypes which belong to mGluR class II or III, such as (2s, 1′R,2′R,3′R)-2-(2,3-dicarboxycyclopropyl)-glycine (DCG-IV) (specific for subtypes mGluR2 or 3) or L-2-amino-4-phosphonobutanoate and L-serine-O-phosphate (specific for subtypes mGluR4, 6 or 7), were highly potent and efficacious in protecting cultured cortical neurons against toxicity induced by either a transient exposure to N-methyl-D-aspartate (NMDA) or a prolonged exposure to kainate. In contrast, agonists that preferentially activate class I mGluR subtypes (mGluR1 or 5), such as quisqualate or trans-azetidine-2,3-dicarboxylic acid, were inactive. DCG-IV was still neuroprotective when applied to cultures after the toxic pulse with NMDA. This delayed rescue effect was associated with a reduction in the release of endogenous glutamate, a process that contributes to the maturation of neuronal damage. We conclude that agonists of class II or III mGluRs are of potential interest in the experimental therapy of acute or chronic neurodegenerative disorders.
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Neuron damage induced by some potent kainoids and neuroprotective action of new agonists for metabotropic glutamate receptors.
European neurology, 1994Co-Authors: H. ShinozakiAbstract:Selective and characteristic neuron damage induced by acromelic acid, a potent kainate analogue, was investigated in comparison to a kainate-induced one. A single systemic injection of acromelic acid A caused behavioral and pathological effects distinct from those seen after systemic kainate. There was an initial marked tonic extension of the rat hindlimb, often followed by convulsions and, in surviving rats, by a transient flaccid paralysis and ultimately, a persistent spastic paraplegia. Pathological examination suggested specific lesions of interneurons in the lower spinal cord with little or no damage to the hippocampal neurons preferentially affected by systemic kainate. Another agonist for kainate-type receptors, which is not a kainoid, demonstrated neurological symptoms and neuron damage quite similar to those of kainate. Pharmacological actions of our newly developed agonists for metabotropic glutamate receptors were described with special reference to kainate excitotoxicity. Intraventricular DCG-IV, a new agonist, caused selective neuron damage in the cingulate cortex and the hippocampal subiculum at relatively high doses, but other agonists did not cause neuron damage in the rat. DCG-IV considerably alleviated the kainate-induced limbic seizures. At relatively low doses, DCG-IV protected some kinds of neurons in the hippocampal CA3 and the amygdala against kainate neurotoxicity, when intraventricularly injected to the rat. These new agonists would provide useful probe for elucidating the mechanism underlying neuron damage induced by kainate-type agonists.
Jürgen Wichmann - One of the best experts on this subject based on the ideXlab platform.
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Characterization of (2S, 2'R, 3'R)-2-(2', 3'-[3H]-dicarboxycyclopropyl)glycine binding in rat brain
Journal of neurochemistry, 2002Co-Authors: Vincent Mutel, Jürgen Wichmann, Geo Adam, Sylvie Chaboz, John A. Kemp, Agnès Klingelschmidt, Jürg Messer, Thomas Johannes Woltering, J.g. RichardsAbstract:[(2S,2'R,3'R)-2-(2',3'-[3H]Dicarboxycyclopropyl)glycine ([3H]DCG IV) binding was characterized in vitro in rat brain cortex homogenates and rat brain sections. In cortex homogenates, the binding was saturable and the saturation isotherm indicated the presence of a single binding site with a K(D) value of 180 +/- 33 nM and a Bmax of 780 +/- 70 fmol/mg of protein. The nonspecific binding, measured using 100 microM LY354740, was DCG IV = (2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid > (2S,1'S,2'S)-2-methyl-2-(2-carboxycyclopropyl)glycine > L-glutamate = ibotenate > quisqualate > (RS)-alpha-methyl-4-phosphonophenylglycine = L(+)-2-amino-3-phosphonopropionic acid > (S)-alpha-methyl-4-carboxyphenylglycine > (2S)-alpha-ethylglutamic acid > L(+)-2-amino-4-phosphonobutyric acid. N-Acetyl-L-aspartyl-L-glutamic acid inhibited the binding in a biphasic manner with an IC50 of 0.2 microM for the high-affinity component. The binding was also affected by GTPgammaS, reducing agents, and CdCl2. In parasagittal sections of rat brain, a high density of specific binding was observed in the accessory olfactory bulb, cortical regions (layers 1, 3, and 4 > 2, 5, and 6), caudate putamen, molecular layers of the hippocampus and dentate gyrus, subiculum, presubiculum, retrosplenial cortex, anteroventral thalamic nuclei, and cerebellar granular layer, reflecting its preferential (perhaps not exclusive) affinity for pre- and postsynaptic metabotropic glutamate mGlu2 receptors. Thus, the pharmacology, tissue distribution, and sensitivity to GTPgammaS show that [3H]DCG IV binding is probably to group II metabotropic glutamate receptors in rat brain.
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Synthesis of (2S, 2'R, 3'R)-2-(1'-[3H], 2', 3'-dicarboxylcyclopropyl)-glycine ([3H]-DCG-IV)
Journal of Labelled Compounds and Radiopharmaceuticals, 2000Co-Authors: Jürgen Wichmann, Philipp Huguenin, Geo AdamAbstract:The conformationally restricted analog of L-glutamic acid (L-Glu, 1) (2S,2′R,3′R)-2-(2′,3′-dicarboxylcyclopropyl)-glycine (DCG-IV, 2) is a potent group II mGluR agonist. In order to study the distribution of group II mGluRs in the brain and to establish a radioligand binding assay we have developed a synthesis of [3H]-DCG-IV (2a). The key intermediate, α-bromo aldehyde 7, was prepared in four steps starting from (−)-Fiest's acid (3). The incorporation of tritium was performed by reaction of 7 with tri-n-butyltin tritide to give 8, which was transformed in two steps into 2a. Copyright © 2000 John Wiley & Sons, Ltd.
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A Short and Efficient Synthesis of (2S,2′R,3′R)-2-(2′,3′-Dicarboxylcyclopropyl)glycine (DCG-IV)
European Journal of Organic Chemistry, 1999Co-Authors: Jürgen Wichmann, Geo AdamAbstract:Feist′s acid (5) was used in enantiomerically pure form as starting material for the synthesis of (2S,2′R,3′R)-2-(2′,3′-dicarboxylcyclopropyl)-glycine (DCG-IV) (2). This conformationally restricted analog of L-glutamic acid (L-Glu) 1 is a potent group II mGlu receptor agonist.
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Characterization of [3H]-(2S,2′R,3′R)-2-(2′,3′-dicarboxy- cyclopropyl)glycine ([3H]-DCG IV) binding to metabotropic mGlu2 receptor-transfected cell membranes
British journal of pharmacology, 1998Co-Authors: Jayne Cartmell, Hervé Schaffhauser, Geo Adam, Sylvie Chaboz, Robert Henningsen, John A. Kemp, Agnès Klingelschmidt, Veit Metzler, Frederick J. Monsma, Jürgen WichmannAbstract:1. The binding of the new selective group II metabotropic glutamate receptor radioligand, [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine ([3H]-DCG IV), was characterized in rat mGlu2 receptor-transfected CHO cell membranes. 2. [3H]-DCG IV binding was pH-dependent, but was not sensitive to temperature. Saturation analysis showed the presence of a single binding site, with a Kd value of 160 nM and a Bmax value of 10 pmol mg(-1) protein. Binding was not sensitive to Na+-dependent glutamate uptake blockers or Cl-dependent glutamate binding inhibitors. Furthermore, up to concentrations of 1 mM, the glutamate ionotropic receptor agonists, N-methyl-D-aspartic acid (NMDA), (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate, did not affect [3H]-DCG IV binding. 3. Of the compounds observed to inhibit [3H]-DCG IV binding, the most potent were the recently described selective group II agonist, (+)-2-aminobicyclo-[3.1.0]hexane-2,6-dicarboxylate (LY 354740; Ki value 16 nM) and antagonist, 2-amino-2-(2-carboxycyclopropan-1-yl)-3-(dibenzopyran-4-yl) propanoic acid (LY 341495; Ki value 19 nM). As expected, for a G-protein-coupled receptor, guanosine-5'-O-(3-thiotriphosphate) (GTPgammaS) inhibited [3H]-DCG IV binding in a concentration-dependent manner, with an IC50 value of 12 nNM. 4. A highly significant correlation was observed between the potencies of compounds able to inhibit [3H]-DCG IV binding and potencies obtained for agonist activity in a GTPgamma35S binding functional assay. In addition, these studies identified a number of compounds with previously unknown activity at mGlu2 receptors, including L(+)-2-amino-3-phosphonopropionic acid (L-AP3), L(+)-2-amino-5-phosphonopentanoic acid (L-AP5), 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP), N-acetyl-L-aspartyl-L-glutamic acid (NAAG) and (RS)-alpha-methylserine-O-phosphate (MSOP).
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mGluR-evoked augmentation of receptor-mediated cyclic AMP formation in neonatal and adult rat striatum
British journal of pharmacology, 1997Co-Authors: Jayne Cartmell, Hervé Schaffhauser, Jürgen Wichmann, Vincent MutelAbstract:The effects of selective agonists at group I, II and III metabotropic glutamate receptors (mGluRs) on adenosine A2 receptor-mediated cyclic AMP formation were compared in cross-chopped slices of adult and neonatal (8 days old) rat striatum, in the presence of 1 u ml−1 adenosine deaminase. The group II selective agonist, (2S,1R,2R,3R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), elicited a potentiation of 5′-N-ethylcarboxamidoadenosine (NECA)-stimulated cyclic AMP production with similar potencies in adult (EC50 value 122±35 nM) and neonatal (EC50 value 285±6 nM) brain. In contrast, the group I selective agonist (S)-dihydroxyphenylglycine ((S)-DHPG) augmented the NECA cyclic AMP response in neonatal striatum (EC50 value 9±1 μM), but at a concentration of 100 μM, (S)-DHPG failed to affect the NECA response in adult striatal slices. The potentiation evoked by (S)-DHPG was specific for group I mGluRs as (2S,3S,4S,)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG), a group II antagonist, was ineffective on the (S)-DHPG (100 μM) response at a concentration (500 μM) which reversed a similar augmentation elicited by DCG-IV (300 nM). Furthermore, a protein kinase C inhibitor (Ro 31-8220, 10 μM) markedly reversed the effect of (S)-DHPG without affecting the response to DCG-IV. The mGluR agonist (2S,3S,4S,)-α-(carboxycyclopropyl)glycine (L-CCG-I), elicited a greater potentiation of NECA-stimulated cyclic AMP production in neonatal striatum in comparison with that observed in adult rat brain. Moreover, EC50 values obtained from adult and neonatal striatum were 2±1 μM and 9±1 μM, respectively. These differences in potency might reflect co-activation of both group I and group II mGluRs by L-CCG-I in neonatal striatum. Distinct patterns of mGluR expression in various brain areas might account for previous conflicting data on the nature of the mGluR able to evoke such potentiated responses.
Henry F. Bradford - One of the best experts on this subject based on the ideXlab platform.
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Anticonvulsant and glutamate release-inhibiting properties of the highly potent metabotropic glutamate receptor agonist (2S,2′R,3′R)-2-(2′,3′-dicarboxycyclopropyl)glycine (DCG-IV)
Brain Research, 1998Co-Authors: Philip J.e. Attwell, David E. Jane, Martin J. Croucher, N. Singh Kent, Henry F. BradfordAbstract:Abstract The anticonvulsant effects of intracerebral administration of the highly potent group II metabotropic glutamate receptor agonist, DCG-IV, were tested in fully kindled rats following daily electrical stimulation of the basolateral amygdala. The agonist caused a dose-dependent increase in the generalized seizure threshold (GST) of these seizure susceptible animals within the dose range tested (0.01–1.0 nmol). The estimated GST 100 value (dose causing a 100% increase in GST) for this effect was 0.22 nmol. The anti-seizure activity of DCG-IV was fully inhibited in the presence of the group II metabotropic glutamate receptor antagonist (2 S ,1′ S ,2′ S )-2-methyl-2-(carboxycyclopropyl)glycine (MCCG; 40 nmol), while MCCG alone showed no significant inhibitory effect on seizure activity. DCG-IV also powerfully inhibited depolarization-induced release of [ 3 H ] d -aspartate from rat cerebrocortical synaptosomes, with an IC 50 value of 0.39 μM. In this respect, DCG-IV was approximately 70-fold more potent than the clinically effective anticonvulsant drug lamotrigine (IC 50 =27.7 μM), a proposed neurotransmitter release inhibitor known to inhibit glutamate release, also tested in this assay. These findings demonstrate the high potency of DCG-IV as an anticonvulsant agent and confirm a key role for group II metabotropic glutamate receptors in the control of seizure activity via their modulatory action on neuronal glutamate release.
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Anticonvulsant and glutamate release-inhibiting properties of the highly potent metabotropic glutamate receptor agonist (2S,2'R, 3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV).
Brain research, 1998Co-Authors: Philip J.e. Attwell, David E. Jane, Martin J. Croucher, N Singh Kent, Henry F. BradfordAbstract:The anticonvulsant effects of intracerebral administration of the highly potent group II metabotropic glutamate receptor agonist, DCG-IV, were tested in fully kindled rats following daily electrical stimulation of the basolateral amygdala. The agonist caused a dose-dependent increase in the generalized seizure threshold (GST) of these seizure susceptible animals within the dose range tested (0. 01-1.0 nmol). The estimated GST100 value (dose causing a 100% increase in GST) for this effect was 0.22 nmol. The anti-seizure activity of DCG-IV was fully inhibited in the presence of the group II metabotropic glutamate receptor antagonist (2S,1'S, 2'S)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG; 40 nmol), while MCCG alone showed no significant inhibitory effect on seizure activity. DCG-IV also powerfully inhibited depolarization-induced release of [3H]D-aspartate from rat cerebrocortical synaptosomes, with an IC50 value of 0.39 microM. In this respect, DCG-IV was approximately 70-fold more potent than the clinically effective anticonvulsant drug lamotrigine (IC50=27.7 microM), a proposed neurotransmitter release inhibitor known to inhibit glutamate release, also tested in this assay. These findings demonstrate the high potency of DCG-IV as an anticonvulsant agent and confirm a key role for group II metabotropic glutamate receptors in the control of seizure activity via their modulatory action on neuronal glutamate release.
Geo Adam - One of the best experts on this subject based on the ideXlab platform.
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Characterization of (2S, 2'R, 3'R)-2-(2', 3'-[3H]-dicarboxycyclopropyl)glycine binding in rat brain
Journal of neurochemistry, 2002Co-Authors: Vincent Mutel, Jürgen Wichmann, Geo Adam, Sylvie Chaboz, John A. Kemp, Agnès Klingelschmidt, Jürg Messer, Thomas Johannes Woltering, J.g. RichardsAbstract:[(2S,2'R,3'R)-2-(2',3'-[3H]Dicarboxycyclopropyl)glycine ([3H]DCG IV) binding was characterized in vitro in rat brain cortex homogenates and rat brain sections. In cortex homogenates, the binding was saturable and the saturation isotherm indicated the presence of a single binding site with a K(D) value of 180 +/- 33 nM and a Bmax of 780 +/- 70 fmol/mg of protein. The nonspecific binding, measured using 100 microM LY354740, was DCG IV = (2S,1'S,2'S)-2-(2-carboxycyclopropyl)glycine > (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid > (2S,1'S,2'S)-2-methyl-2-(2-carboxycyclopropyl)glycine > L-glutamate = ibotenate > quisqualate > (RS)-alpha-methyl-4-phosphonophenylglycine = L(+)-2-amino-3-phosphonopropionic acid > (S)-alpha-methyl-4-carboxyphenylglycine > (2S)-alpha-ethylglutamic acid > L(+)-2-amino-4-phosphonobutyric acid. N-Acetyl-L-aspartyl-L-glutamic acid inhibited the binding in a biphasic manner with an IC50 of 0.2 microM for the high-affinity component. The binding was also affected by GTPgammaS, reducing agents, and CdCl2. In parasagittal sections of rat brain, a high density of specific binding was observed in the accessory olfactory bulb, cortical regions (layers 1, 3, and 4 > 2, 5, and 6), caudate putamen, molecular layers of the hippocampus and dentate gyrus, subiculum, presubiculum, retrosplenial cortex, anteroventral thalamic nuclei, and cerebellar granular layer, reflecting its preferential (perhaps not exclusive) affinity for pre- and postsynaptic metabotropic glutamate mGlu2 receptors. Thus, the pharmacology, tissue distribution, and sensitivity to GTPgammaS show that [3H]DCG IV binding is probably to group II metabotropic glutamate receptors in rat brain.
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Synthesis of (2S, 2'R, 3'R)-2-(1'-[3H], 2', 3'-dicarboxylcyclopropyl)-glycine ([3H]-DCG-IV)
Journal of Labelled Compounds and Radiopharmaceuticals, 2000Co-Authors: Jürgen Wichmann, Philipp Huguenin, Geo AdamAbstract:The conformationally restricted analog of L-glutamic acid (L-Glu, 1) (2S,2′R,3′R)-2-(2′,3′-dicarboxylcyclopropyl)-glycine (DCG-IV, 2) is a potent group II mGluR agonist. In order to study the distribution of group II mGluRs in the brain and to establish a radioligand binding assay we have developed a synthesis of [3H]-DCG-IV (2a). The key intermediate, α-bromo aldehyde 7, was prepared in four steps starting from (−)-Fiest's acid (3). The incorporation of tritium was performed by reaction of 7 with tri-n-butyltin tritide to give 8, which was transformed in two steps into 2a. Copyright © 2000 John Wiley & Sons, Ltd.
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A Short and Efficient Synthesis of (2S,2′R,3′R)-2-(2′,3′-Dicarboxylcyclopropyl)glycine (DCG-IV)
European Journal of Organic Chemistry, 1999Co-Authors: Jürgen Wichmann, Geo AdamAbstract:Feist′s acid (5) was used in enantiomerically pure form as starting material for the synthesis of (2S,2′R,3′R)-2-(2′,3′-dicarboxylcyclopropyl)-glycine (DCG-IV) (2). This conformationally restricted analog of L-glutamic acid (L-Glu) 1 is a potent group II mGlu receptor agonist.
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Characterization of [3H]-(2S,2′R,3′R)-2-(2′,3′-dicarboxy- cyclopropyl)glycine ([3H]-DCG IV) binding to metabotropic mGlu2 receptor-transfected cell membranes
British journal of pharmacology, 1998Co-Authors: Jayne Cartmell, Hervé Schaffhauser, Geo Adam, Sylvie Chaboz, Robert Henningsen, John A. Kemp, Agnès Klingelschmidt, Veit Metzler, Frederick J. Monsma, Jürgen WichmannAbstract:1. The binding of the new selective group II metabotropic glutamate receptor radioligand, [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine ([3H]-DCG IV), was characterized in rat mGlu2 receptor-transfected CHO cell membranes. 2. [3H]-DCG IV binding was pH-dependent, but was not sensitive to temperature. Saturation analysis showed the presence of a single binding site, with a Kd value of 160 nM and a Bmax value of 10 pmol mg(-1) protein. Binding was not sensitive to Na+-dependent glutamate uptake blockers or Cl-dependent glutamate binding inhibitors. Furthermore, up to concentrations of 1 mM, the glutamate ionotropic receptor agonists, N-methyl-D-aspartic acid (NMDA), (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate, did not affect [3H]-DCG IV binding. 3. Of the compounds observed to inhibit [3H]-DCG IV binding, the most potent were the recently described selective group II agonist, (+)-2-aminobicyclo-[3.1.0]hexane-2,6-dicarboxylate (LY 354740; Ki value 16 nM) and antagonist, 2-amino-2-(2-carboxycyclopropan-1-yl)-3-(dibenzopyran-4-yl) propanoic acid (LY 341495; Ki value 19 nM). As expected, for a G-protein-coupled receptor, guanosine-5'-O-(3-thiotriphosphate) (GTPgammaS) inhibited [3H]-DCG IV binding in a concentration-dependent manner, with an IC50 value of 12 nNM. 4. A highly significant correlation was observed between the potencies of compounds able to inhibit [3H]-DCG IV binding and potencies obtained for agonist activity in a GTPgamma35S binding functional assay. In addition, these studies identified a number of compounds with previously unknown activity at mGlu2 receptors, including L(+)-2-amino-3-phosphonopropionic acid (L-AP3), L(+)-2-amino-5-phosphonopentanoic acid (L-AP5), 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP), N-acetyl-L-aspartyl-L-glutamic acid (NAAG) and (RS)-alpha-methylserine-O-phosphate (MSOP).