Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: CAS:6893-26-1 (glutamate)
 73,096 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Antagonists of glutamate N-methyl-D-aspartate (NMDA) subtype receptor inhibit the development of tolerance to the antinociceptive effects of opioids. Another way to inhibit the function of glutamate receptors is the stimulation of presynaptic metabotropic group II (mGluRII) receptors. Because LY354740 ((+)-2-aminobicyclo [3,1,0] hexane-2,6-dicarboxylic acid) is the first systemically active agonist of group II mGlu receptors, we investigated if this compound might inhibit the development of tolerance to antinociceptive effects of morphine and fentanyl. 2. As assessed by cumulative dose-response approach in the tail-flick test, administration of 10 mg kg(-1) morphine bid s.c. to male Albino Swiss mice for 6 days, right-shifted morphine dose-response curve by approximately 4 fold. In a separate group of mice, 12 injections of 0.04 mg kg(-1) of fentanyl over 3 days, right-shifted fentanyl dose-response curve by approximately 3.3 fold. 3. In experiment 1, LY354740 (1 and 10, but not 0.1 mg kg(-1)) as well as the reference compound, an uncompetitive NMDA receptor antagonist memantine (7.5 mg kg(-1)) inhibited the development of morphine tolerance. Neither LY354740 (10 mg kg(-1)) nor memantine (7.5 mg kg(-1)) affected the development of tolerance to fentanyl. In experiment 2, neither LY354740 (1 and 10 mg kg(-1)) nor memantine (7.5 mg kg(-1)) affected the tail-flick antinociceptive response, or the acute antinociceptive effect of morphine. 4. The present results are the first to suggest that the development of antinociceptive morphine tolerance may be inhibited by metabotropic group II glutamate agonist.
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PMID:Selective agonist of group II glutamate metabotropic receptors, LY354740, inhibits tolerance to analgesic effects of morphine in mice. 1090 86

G-protein-coupled metabotropic glutamate receptors (mGluRs) are being implicated in various forms of neuroplasticity and CNS disorders. This study examined whether the sensitivities of mGluR agonists are modulated in a distinct fashion in different models of synaptic plasticity, specifically, kindling and chronic cocaine treatment. The influence of kindling and chronic cocaine exposure in vivo was examined in vitro on the modulation of synaptic transmission by group II and III metabotropic glutamate receptors using whole cell voltage-clamp recordings of central amygdala (CeA) neurons. Synaptic transmission was evoked by electrical stimulation of the basolateral amygdala (BLA) and ventral amygdaloid pathway (VAP) afferents in brain slices from control rats and from rats treated with cocaine or exposed to three to five stage-five kindled seizures. This study shows that after chemical stimulation with chronic cocaine exposure or after electrical stimulation with kindling the receptor sensitivities for mGluR agonists are altered in opposite ways. In slices from control rats, group II agonists, (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG1) and (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740), depressed neurotransmission more potently at the BLA-CeA than at the VAP-CeA synapse while group III agonist, L(+)-2-amino-4-phosphonobutyrate (LAP4), depressed neurotransmission more potently at the VAP-CeA synapse than at the BLA-CeA. These agonist actions were not seen (were absent) in amygdala neurons from chronic cocaine-treated animals. In contrast, after kindling, concentration response relationships for LCCG1 and LAP4 were shifted to the left, suggesting that sensitivity to these agonists is increased. Except at high concentrations, LCCG1, LY354740, and LAP4 neither induced membrane currents nor changed current-voltage relationships. Loss of mGluR inhibition with chronic cocaine treatment may contribute to counter-adaptive changes including anxiety and depression in cocaine withdrawal. Drugs that restore the inhibitory effects of group II and III mGluRs may be novel tools in the treatment of cocaine dependence. The enhanced sensitivity to group II and III mGluR agonists in kindling is similar to that recorded at the lateral to BLA synapse in the amygdala where they reduce epileptiform bursting. These findings suggest that drugs modifying mGluRs may prove useful in the treatment of cocaine withdrawal or epilepsy.
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PMID:Cocaine and kindling alter the sensitivity of group II and III metabotropic glutamate receptors in the central amygdala. 1093 3

The heterogeneous family of G-protein-coupled metabotropic glutamate receptors (mGluRs) provides excitatory and inhibitory controls of synaptic transmission and neuronal excitability in the nervous system. Eight mGluR subtypes have been cloned and are classified in three subgroups. Group I mGluRs can stimulate phosphoinositide hydrolysis and activate protein kinase C whereas group II (mGluR2 and 3) and group III (mGluR4, 6, 7, and 8) mGluRs share the ability to inhibit cAMP formation. The present study examined the roles of groups II and III mGluRs in the processing of brief nociceptive information and capsaicin-induced central sensitization of primate spinothalamic tract (STT) cells in vivo. In 11 anesthetized male monkeys (Macaca fascicularis), extracellular recordings were made from 21 STT cells in the lumbar dorsal horn. Responses to brief (15 s) cutaneous stimuli of innocuous (brush), marginally and distinctly noxious (press and pinch, respectively) intensity were recorded before, during, and after the infusion of group II and group III mGluR agonists into the dorsal horn by microdialysis. Different concentrations were applied for at least 20 min each (at 5 microliter/min) to obtain cumulative concentration-response relationships. Values in this paper refer to the drug concentrations in the microdialysis fibers; actual concentrations in the tissue are about three orders of magnitude lower. The agonists were also applied at 10-25 min after intradermal capsaicin injection. The group II agonists (2S,1'S,2'S)-2-(carboxycyclopropyl)glycine (LCCG1, 1 microM-10 mM, n = 6) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4, 6-dicarboxylate (LY379268; 1 microM-10 mM, n = 6) had no significant effects on the responses to brief cutaneous mechanical stimuli (brush, press, pinch) or on ongoing background activity. In contrast, the group III agonist L(+)-2-amino-4-phosphonobutyric acid (LAP4, 0. 1 microM-10 mM, n = 6) inhibited the responses to cutaneous mechanical stimuli in a concentration-dependent manner, having a stronger effect on brush responses than on responses to press and pinch. LAP4 did not change background discharges significantly. Intradermal injections of capsaicin increased ongoing background activity and sensitized the STT cells to cutaneous mechanical stimuli (ongoing activity > brush > press > pinch). When given as posttreatment, the group II agonists LCCG1 (100 microM, n = 5) and LY379268 (100 microM, n = 6) and the group III agonist LAP4 (100 microM, n = 6) reversed the capsaicin-induced sensitization. After washout of the agonists, the central sensitization resumed. Our data suggest that, while activation of both group II and group III mGluRs can reverse capsaicin-induced central sensitization, it is the actions of group II mGluRs in particular that undergo significant functional changes during central sensitization because they modulate responses of sensitized STT cells but have no effect under control conditions.
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PMID:Groups II and III metabotropic glutamate receptors differentially modulate brief and prolonged nociception in primate STT cells. 1111 Aug 27

Exposure of rats to a single session of foot shocks sensitizes behavioral responses to novel stimuli. There is evidence that metabotropic glutamate (mGlu) receptors play a role in sensitization processes. In the present study, we investigated the role of mGlu(2/3) receptors in the long-term (14 days) increase in defensive withdrawal behavior after a single session of foot shocks. Exposure to foot shocks increased defensive withdrawal behavior. The mGlu(2/3) receptor agonist LY354740 ((1S,2S,5R,6S)-(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid, 0.1 mg/kg, i.p.) normalized the increased latency and the decreased time in the light of the preshocked rats. We conclude that activation of mGlu(2/3) receptors attenuates the foot shock-induced expression of behavioral sensitization.
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PMID:LY354740 attenuates the expression of long-term behavioral sensitization induced by a single session of foot shocks. 1152 74

Metabotropic glutamate (mGlu) receptors are a family of G-protein-coupled receptors that play central roles as modulators of both glutamatergic and other major neurotransmitter systems in CNS. Using molecular modeling, site-directed mutagenesis, [(3)H]LY354740 binding, [(35)S]GTPgammaS binding, and activation of GIRK current, we have been able to identify residues crucial for the binding of LY354740 and glutamate to rat mGlu2 receptors. Several of the crucial residues located in the binding site (Arg-57, Tyr-144, Tyr-216, Asp-295) have not been identified previously. We propose that the gamma-carboxyl group of LY354740 forms H-bonds to Arg-57, whereas the alpha-carboxyl group forms an H-bond with the hydroxyl group of Ser-145. The alpha-amino group of LY354740 forms H-bonds to Asp-295 and to the side-chain hydroxyl group of Thr-168. In addition, Tyr-144 may establish a hydrophobic (C-H/pi)-interaction with the bicyclo-hexane ring of LY354740. Furthermore, the mutation of residues Ser-148 and Arg-183, which are too remote for a direct interaction, affected the ligand affinity dramatically. These results suggest that Ser-148 and Arg-183 may be important for the 3D structure and/or are involved in closure of the domain. Finally, Asp-146, which is also remote from the binding site, was shown to be involved in the differential binding affinity of [(3)H]LY354740 for mGlu2 versus mGlu3 receptors. All the mGlu receptors except mGlu2 are activated by Ca(2+) and have serine instead of aspartic acid at this position, which suggests a critical role of this aspartic acid residue in the binding properties of this unique receptor.
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PMID:Identification of essential residues involved in the glutamate binding pocket of the group II metabotropic glutamate receptor. 1164 22

(+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740) is a conformationally restricted glutamate analogue that is a potent, selective and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties. Herein, we describe a stereoselective and highly efficient synthesis of its 3-beta fluoro derivative using the Corey-Link methodology to create the amino acid stereogenic center.
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PMID:Stereoselective synthesis of 2-amino-3-fluoro bicyclo[3.1.0]hexane-2,6-dicarboxylic acid. 1174 91

Methamphetamine (MA), a widely used drug of abuse, produces oxidative damage of nigrostriatal dopaminergic terminals. We examined the effect of subtype-selective ligands of metabotropic glutamate (mGlu) receptors on MA neurotoxicity in mice. MA (5 mg/kg, i.p.; injected three times, every 2 hr) induced, 5 d later, a substantial degeneration of striatal dopaminergic terminals associated with reactive gliosis. MA toxicity was primarily attenuated by the coinjection of the noncompetitive mGlu5 receptor antagonists 2-methyl-6-(phenylethynyl)pyridine and (E)-2-methyl-6-styrylpyridine both at 10 mg/kg, i.p.). In contrast, the mGlu1 receptor antagonist 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester (10 mg/kg, i.p.), and the mGlu2/3 receptor agonist (-)-2-oxa-4-aminocyclo[3.1.0]hexane-4,6-dicarboxylic acid (1 mg/kg, i.p.), failed to affect MA toxicity. mGlu5 receptor antagonists reduced the production of reactive oxygen species but did not reduce the acute stimulation of dopamine release induced by MA both in striatal synaptosomes and in the striatum of freely moving mice. We conclude that endogenous activation of mGlu5 receptors enables the development of MA neurotoxicity and that mGlu5 receptor antagonists are neuroprotective without interfering with the primary mechanism of action of MA.
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PMID:Selective blockade of mGlu5 metabotropic glutamate receptors is protective against methamphetamine neurotoxicity. 1189 53

Previous studies have shown that 5-hydroxytryptamine(2A) (5-HT(2A)) receptor activation induces changes in the pattern of brain-derived neurotrophic factor (BDNF) mRNA expression in the neocortex and hippocampus, and that 5-HT(2A) receptor blockade interferes with the induction of BDNF mRNA by stress. Recent studies have also shown that activation of metabotropic glutamate group II (mGlu2/3) receptors suppresses 5-HT(2A) receptor-stimulated excitatory postsynaptic potentials/currents (EPSP/Cs) in pyramidal neurons in medial prefrontal cortex. Conversely, blockade of mGlu2/3 receptors enhances 5-HT-induced EPSCs. The current study examined the effects of the highly selective mGlu2/3 agonist (1S,2S,5R,6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and the mGlu2/3 antagonist 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) on BDNF mRNA expression in medial prefrontal cortex induced by the hallucinogen and 5-HT(2A/2B/2C) agonist 1-(2,5-dimethoxy-4-iodophenethyl)-2-aminopropane (DOI). LY354740 (0.1-10 mg/kg) dose-dependently suppressed DOI-induced BDNF mRNA levels in medial prefrontal cortex. In contrast, the mGlu2/3 antagonist LY341495 (1 mg/kg) enhanced DOI-induced BDNF mRNA levels. BDNF mRNA expression was not altered by administration of the mGlu agonist or the antagonist alone. These results are discussed with respect to a potential role for group II mGlu agonists in the treatment of depression and schizophrenia.
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PMID:Modulation of DOI-induced increases in cortical BDNF expression by group II mGlu receptors. 1211 85

Recent findings have shown that dendritically released dopamine (DA) plays an important modulatory role in the substantia nigra pars reticulata (SNr). It is therefore possible that the loss of DA observed in Parkinson's disease (PD) could hold important consequences for nigral function. Previously, we have shown that activation of presynaptically localized group II metabotropic glutamate receptors (mGluRs) inhibits excitatory transmission at the subthalamic nucleus (STN)-SNr synapse and that activation of presynaptically localized group III mGluRs decreases excitatory and inhibitory transmission in the SNr. To test the hypothesis that nigral DA can modulate mGluR function in the SNr, we performed whole-cell patch-clamp recordings from gamma-aminobutyric acidergic SNr neurons in slices obtained from rats that were acutely reserpinized. In slices obtained from reserpinized animals, the effect of group II mGluR activation by the selective agonist (+)-2-aminobicyclo[3.1.0]-hexane-2,6-dicarboxylate monohydrate (LY354740) (100 nM), but not group III mGluR activation [L-(+)-2-amino-4-phosphonobutyric acid, L-AP4, 500 microM], at STN-SNr synapses is significantly decreased. This effect could be mimicked in control slices by prior bath application of haloperidol (20 microM) and R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH23390) (20 microM) but not sulpiride (50 microM). Furthermore, application of dopamine (100 microM) and (+/-)-6-chloro-7,8-dyhydroxy-3allyl-1-phenyl-2,3,4,5-tetra-hydro-1H-benzazepine (SKF82958) (1 microM) but not quinpirole (10 microM) could rescue the group II mGluR effect in reserpinized slices. The effect of group III mGluR activation (L-AP4, 100 microM) on inhibitory synaptic transmission was also significantly reduced in slices from reserpine-treated animals. This effect was mimicked by haloperidol (20 microM), SCH23390 (20 microM), and sulpiride (50 microM) in control slices. Thus, in a Parkinsonian state, the loss of nigral DA may add to the overall pathophysiological changes in basal ganglia output.
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PMID:Dopamine modulates the function of group II and group III metabotropic glutamate receptors in the substantia nigra pars reticulata. 1213 Jul

Signal transduction mechanisms of group II metabotropic glutamate receptors (mGlu(2/3)) remains a matter of some controversy, therefore we sought to gain new insights into its regulation by studying cAMP production in cultured neurons and astrocytes, and by examining inter-relationships of mGlu(2/3)-induced signalling with cellular calcium and various signalling cascades. mGlu(2/3) agonists 2R,4R-4-aminopyrrolidine-2,4-dicarboxylic acid (2R,4R-APDC) and (-)-2-oxa-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid (LY379268) inhibited 10 microM forskolin-stimulated production of cAMP in murine cortical neurons, striatal neurons and forebrain astrocytes in the absence of extracellular Ca(2+). These agonists potentiated cAMP production in the presence of 1.8 mM Ca(2+) in astrocytes only. This potentiation was dependent on the extracellular Ca(2+) concentration (0.001-10 mM) and inhibited by the mGlu(2/3) antagonist LY341495 (1 microM), adenosine deaminase (1 U/ml) and the adenosine A(2A) receptor antagonist ZM241385 (1 microM). Pre-incubation with the phospholipase C (PLC) inhibitor U73122 (10 microM), L-type Ca(2+)-channel blockers nifedipine (1 microM) and nimodipine (1 microM), the calmodulin kinase II (CaMKII) inhibitor KN-62 (10 microM) or pertussis toxin (100 ng/ml) inhibited this potentiation. In the absence of 1.8 mM Ca(2+), thapsigargin (1 microM) facilitated the potentiation of cAMP production. Measurement of the Ca(2+)-binding dye Fluo-3/AM showed that, compared to Ca(2+)-free conditions, thapsigargin and 1.8 mM Ca(2+) elevated [Ca(2+)](i) in astrocytes; the latter effect being prevented by L-type Ca(2+)-channel blockers. Potentiation of cAMP production was also demonstrated when astrocytes were stimulated with the beta-adrenoceptor agonist isoprenaline (10 microM) in the presence of 1.8 mM Ca(2+), but not with the adenosine agonist NECA (10 microM) or the group I mGlu receptor agonist DHPG (100 microM). BaCl(2) (1.8 mM) in place of Ca(2+) did not facilitate forskolin-stimulated mGlu(2/3)-potentiation of cAMP. In short, this study in astrocytes demonstrates that under physiological Ca(2+) and adenylate cyclase stimulation an elevation of cAMP production is achieved that is mediated by PLC/IP(3)- and CaMKII-dependent pathways and results in the release of endogenous adenosine which acts at G(s) protein-coupled A(2A) receptors. These findings provide new insights into mGlu(2/3) signalling in astrocytes versus neurons, and which could determine the functional phenotypy of astrocytes under physiological and pathological conditions.
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PMID:Astrocyte mGlu(2/3)-mediated cAMP potentiation is calcium sensitive: studies in murine neuronal and astrocyte cultures. 1221 73


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