Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0036341 (schizophrenia)
 60,220 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We examined the regulation of mGlu2 and mGlu3 metabotropic glutamate receptor signaling prompted by the emerging role of these receptor subtypes as therapeutic targets for psychiatric disorders, such as anxiety and schizophrenia. In transfected human embryonic kidney 293 cells, G-protein-coupled receptor kinase (GRK) 2 and GRK3 fully desensitized the agonist-dependent inhibition of cAMP formation mediated by mGlu3 receptors. In contrast, GRK2 or other GRKs did not desensitize the cAMP response to mGlu2 receptor activation. Desensitization of mGlu3 receptors by GRK2 required an intact kinase activity, as shown by the use of the kinase-dead mutant GRK2-K220R or the recombinant GRK2 C-terminal domain. Overexpression of beta-arrestin1 also desensitized mGlu3 receptors and did not affect the cAMP signaling mediated by mGlu2 receptors. The difference in the regulation of mGlu2 and mGlu3 receptors was signal-dependent because GRK2 desensitized the activation of the mitogen-activated protein kinase pathway mediated by both mGlu2 and mGlu3 receptors. In vivo studies confirmed the resistance of mGlu2 receptor-mediated cAMP signaling to homologous desensitization. Wild-type, mGlu2(-/-), or mGlu3(-/-) mice were treated intraperitoneally with saline or the mixed mGlu2/3 receptor agonist (-)-2-oxa-4-aminobicyclo[3.1.0]-exhane-4,6-dicarboxylic acid (LY379268; 1 mg/kg) once daily for 7 days. Inhibition of forskolin-stimulated cAMP formation by LY379268 was measured in cortical slices prepared 24 h after the last injection. Agonist pretreatment fully desensitized the cAMP response in wild-type and mGlu2(-/-) mice but had no effect in mGlu3(-/-) mice, in which LY379268 could only activate the mGlu2 receptor. We predict the lack of tolerance when mixed mGlu2/3 receptor agonists or selective mGlu2 enhancers are used continually in patients.
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PMID:Regulation of group II metabotropic glutamate receptors by G protein-coupled receptor kinases: mGlu2 receptors are resistant to homologous desensitization. 1916 43

A group II metabotropic glutamate receptor (mGluR) agonist was recently reported to be clinically efficacious against symptoms of schizophrenia [Patil, S.T., Zhang, L., Martenyi, F., Lowe, S.L., Jackson, K.A., Andreev, B.V., Avedisova, A.S., Bardenstein, L.M., Gurovich, I.Y., Morozova, M.A., Mosolov, S.N., Neznanov, N.G., Reznik, A.M., Smulevich, A.B., Tochilov, V.A., Johnson, B.G., Monn, J.A., Schoepp, D.D., 2007. Activation of mGlu2/3 receptors as a new approach to treat schizophrenia: a randomized phase 2 clinical trial. Nature Med 13, 1102-1107]. The endogenous neuropeptide N-acetylaspartylglutamate (NAAG) has been described as an agonist at mGluR2 and mGluR3 [Wroblewska, B., Wroblewski, J.T., Pshenichkin, S., Surin, A., Sullivan, S.E., Neale, J.H., 1997. N-acetylaspartylglutamate selectively activates mGluR3 receptors in transfected cells. J. Neurochem. 69, 174-181; Cartmell, J., Adam, G., Chaboz, S., Henningsen, R., Kemp, J.A., Klingelschmidt, A., Metzler, V., Monsma, F., Schaffhauser, H., Wichmann, J., Mutel, V., 1998. 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. Br. J. Pharmacol. 123, 497-504] and is degraded by the enzyme glutamate carboxypeptidase II (also known as N-acetyl-alpha-linked acidic dipeptidase or NAALADase). Hence, elevating the concentration of endogenous NAAG by inhibition of NAALADase represents a potential strategy for the treatment of schizophrenia via group II mGluR activation. We therefore investigated the activity of NAAG at both rat native and human recombinant mGluRs. We found that NAAG had no effect on synaptic transmission at the medial perforant pathway inputs to the rat dentate gyrus which is known to be sensitive to group II mGluR activation. We proceeded to examine the effects of NAAG at human recombinant mGluR2 and mGluR3 in a cellular G protein-activated K+ channel electrophysiology assay. Furthermore, due to discrepancies in the literature concerning the activity of NAAG at the N-methyl-d-aspartate receptor [NMDAR; Westbrook, G.L., Mayer, M.L., Namboodiri, M.A., Neale, J.H., 1986. High concentrations of N-acetylaspartylglutamate (NAAG) selectively activate NMDA receptors on mouse spinal cord neurons in cell culture. J. Neurosci. 6, 3385-3392; Losi, G., Vicini, S., Neale, J., 2004. NAAG fails to antagonize synaptic and extrasynaptic NMDA receptors in cerebellar granule neurons. Neuropharmacology 46, 490-496], we also tested NAAG at NMDARs in rat hippocampal neurons in culture. We found that a purified NAAG preparation had no effect at mGluR2, mGluR3 or NMDAR. Taken together, these findings do not support a rationale for targeting NAALADase and increasing extracellular NAAG levels as a therapeutic strategy for the treatment of schizophrenia.
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PMID:Effects of N-acetylaspartylglutamate (NAAG) at group II mGluRs and NMDAR. 1928 17

Modulation of glutamatergic neurotransmission by metabotropic glutamate2/3 (mGlu2/3) receptor agonists effectively treats seemingly diverse neuropsychiatric illness such as generalized anxiety disorder and schizophrenia. Activation of adenosine A(1) heteroceptors, like mGlu2 autoreceptors, decreases glutamate release in the medial prefrontal cortex (mPFC) and other limbic brain regions. Previously, we have reported electrophysiological, neurochemical and behavioral evidence for interactions between the 5-hydroxytryptamine(2A) (5-HT(2A)) and mGlu2/3 receptors in the mPFC. The present studies were designed to investigate the effects in rats of adenosine A(1) receptor activation/blockade on a behavior modulated by 5-HT(2A) receptor activation/blockade in the mPFC: head shakes induced in the rat by phenethylamine hallucinogens. An adenosine A(1) receptor agonist, N(6)-cyclohexyladenosine (CHA) suppressed head shakes induced by activation of 5-HT(2A) receptors with the phenethylamine hallucinogen (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI). An adenosine A1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), enhanced DOI-induced head shakes and blocked the suppressant action of an adenosine A(1) receptor agonist on DOI-induced head shakes. Thus, the pattern of activity for an agonist and antagonist at the adenosine A1 receptor with respect to modulating DOI-induced head shakes is similar to the pattern observed with mGlu2/3 receptor agonists and antagonists. These novel observations with an adenosine A(1) receptor agonist suggest that this pharmacological action could contribute to antipsychotic effects in addition to thymoleptic effects.
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PMID:Activation of adenosine(1) (A(1)) receptors suppresses head shakes induced by a serotonergic hallucinogen in rats. 1932 62

Binding of the mGlu2/3 antagonist HYDIA in the closed conformation model of mGlu2 causes repulsive interactions with Y216 in lobe II of the binding pocket, preventing closure of the VFT.Modulation of metabotropic glutamate 2/3 receptors represents a promising target for the treatment of neuropsychiatric disorders such as schizophrenia and depression. The novel mGlu2/3 ligand HYDIA ((1S,2R,3R,5R,6S)-2-amino-3-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylic acid) is a conformationally restricted and hydroxylated glutamate analogue. HYDIA is a potent and selective competitive antagonist of L-glutamate at the mGlu2/3 receptors in spite of being structurally very similar to the bicyclic LY354740, which is a potent and selective mGlu2/3 agonist. By comparing these two ligands, this study delineate the interaction mode of (3)H-HYDIA at the mGlu2 receptor, using both mutagenesis studies and computational modeling. Binding of HYDIA in the closed conformation model of mGlu2 results in repulsive interaction with the Y216 residue, preventing closure of the binding pocket and thus receptor activation. Consequently, HYDIA is proposed to bind in an open conformation model of mGlu2. Mutation of the structurally important Y216 residue in the binding site caused complete loss of affinity of both (3)H-LY354740 and (3)H-HYDIA. T168 in lobe I was shown to have an important role in HYDIA binding, and in the open conformation model this residue is interacting with the amino group of HYDIA. The Y144 residue in lobe I is shown to be engaged in both receptor interlobe binding and ligand interaction. Receptor mutations at this position (Y144G, Y144S and Y144A) showed dramatic impact on binding affinity and functional effect of HYDIA. The mGlu2 receptor mutants with increased structural flexibility at this position, which is crucial for pocket closure, were clearly preferred. These studies highlight the unique properties of the novel (3)H-HYDIA ligand and provide further support to our understanding of binding and signal transduction mechanisms of the mGlu2 receptor.
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PMID:Mutagenesis and molecular modeling of the orthosteric binding site of the mGlu2 receptor determining interactions of the group II receptor antagonist (3)H-HYDIA. 1940 24

Mental disorders, such as depression, anxiety and schizophrenia, has become a large medical and social problem recently. Studies performed in animal tests and early clinical investigations brought a new insight in the pharmacotherapy of these disorders. Latest investigations are focused mainly on the glutamatergic system, a main excitatory amino acid neurotransmitter in the brain. Evidence indicates that metabotropic glutamate receptors ligands have excellent antidepressant, anxiolytic and antipsychotic effects. Metabotopic glutamate receptors (mGlu) divaded into three groups (group I, II and III) are localized on nerve terminals, postsynaptic sites and glial cells and thus they can influence and modulate the action of glutamate on different levels in the synapse. Recent advances in the identification of selective and specific compounds (both ortho- and allosteric ligands), and the generation of transgenic animals enabled to have new insight into the pathophysiology and therapy of mood disorders. At present, the most potent seem to be negative allosteric modulators of the first group (mGlu1 and mGlu5), and positive allosteric modulators of the second (mGlu2 and mGlu3) and third (mGlu4/7/8) group of mGlu receptors.
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PMID:Metabotropic glutamate receptors in the tripartite synapse as a target for new psychotropic drugs. 1942 11

Dopamine D2 receptor blockade has been an obligate mechanism of action present in all medications that effectively treat positive symptoms of schizophrenia (e.g., delusions and hallucinations) and have been approved by regulatory agencies since the 1950s. Blockade of 5-hydroxytryptamine(2A) receptors plays a contributory role in the actions of the second generation of antipsychotic drugs, the so-called atypical antipsychotics. Nevertheless, substantial unmet medical needs remain for the treatment of negative symptoms and cognitive dysfunction. Recognition that dissociative anesthetics block the N-methyl-D-aspartate (NMDA) receptor channel has inspired a search for glutamatergic therapeutic mechanisms because ketamine and phencyclidine are known to induce psychotic-like symptoms in healthy volunteers and exacerbate the symptoms of patients with schizophrenia. Current pathophysiological theories of schizophrenia emphasize that hypofunction of NMDA receptors at critical sites in local circuits modulate the function of a given brain region or control projections from one region to another (e.g., hippocampal-cortical or thalamocortical projections). The demonstration that a metabotropic glutamate 2/3 (mGlu2/3) receptor agonist prodrug decreased both positive and negative symptoms of schizophrenia raised hopes that glutamatergic mechanisms may provide therapeutic advantages. In addition to discussing the activation of mGlu2 receptors with mGlu2/3 receptor agonists or mGlu2 receptor positive allosteric modulators (PAMs), we discuss other methods that may potentially modulate circuits with hypofunctional NMDA receptors such as glycine transporter inhibitors and mGlu5 receptor PAMs. The hope is that by modulating glutamatergic neurotransmission, the dysfunctional circuitry of the schizophrenic brain (both local circuits and long-loop pathways) will be improved.
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PMID:Glutamatergic (N-methyl-D-aspartate receptor) hypofrontality in schizophrenia: too little juice or a miswired brain? 1993 74

The manipulation of glutamate neurotransmission could represent a potential strategy for the pharmacotherapy of schizophrenic symptoms. Preclinical studies suggest that two subtypes of metabotropic glutamate (mGlu) receptors such as mGlu2/3 and mGlu5 receptors have the potential to ameliorate deficits in schizophrenia. In our study we evaluated the role of a non-specific mGlu receptor agonist ((1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid; 1S,3R-ACPD), mGlu5 receptor agonist or positive modulators ((RS)-2-Chloro-5-hydroxyphenylglycine;CHPG; [(3-Fluoro-phenyl)methylene]hydrazone-3-fluorobenzaldehyde; DFB; 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide; CDPPB) and a mGlu2/3 receptor agonist (2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyrdinylmethyl)ethanesulfonamide hydrochloride; LY-487379) on performance in a cognitive task (Active Allothetic Place Avoidance) after sub-chronic administration of 5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)-cyclo-hepten-5,10-imine; MK-801 . The Active Allothetic Place Avoidance task is suitable for assessing the executive function and attention of animals and was previously validated for testing the effect of anti-psychotics. Application of the mGlu2/3 receptor agonist had no effect on cognitive impairment induced by MK-801. However, the mGlu5 receptor agonists ameliorated cognitive impairment induced by MK-801 without affecting locomotion. In conclusion, the mGlu5 receptor agonists could be effective in the treatment of cognitive deficits in patients with schizophrenia. However, the pro-cognitive effect of the agonist of mGlu2/3 receptors was not demonstrated in the present study.
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PMID:The difference in effect of mGlu2/3 and mGlu5 receptor agonists on cognitive impairment induced by MK-801. 2037 Dec 26

Glutamate neurotransmission has been considered as one of pathogenetic factors of schizophrenia though all antipsychotics widely used in modern psychiatric practice are dopamine antagonists. LY2140023 is a selective agonist for metabotropic glutamate 2/3 (mGlu2/3) receptors with antipsychotic effect. In the present study, we have assessed clinical efficacy of LY2140023 in patients with schizophrenia compared to the control group receiving olanzapine in a randomized double-blind placebo-controlled trial. The statistically significant reduction of positive and negative symptoms measured with the PANSS (p<0.001) was observed for both antipsychotics at week 4 of treatment compared to placebo. The treatment with LY2140023 was safe and well-tolerated; treated patients did not differ from the placebo group by hyperprolactinemia and extrapyramidal symptoms, and weight gain. The results suggest that the agonist for 2/3 (mGlu2/3) receptors has antipsychotic properties and provides a new, alternative to dopamine agonists, method for pharmacotherapy of schizophrenia.
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PMID:[The use of mGlu2/3 receptors as a new approach to treat schizophrenia: results of a randomized double-blind trial]. 2063 52

Metabotropic glutamate receptors (mGlu receptors) have emerged as new therapeutic targets for psychiatric disorders, such as schizophrenia, depression and anxiety with their regulatory roles in glutamatergic transmissions. To date, several ligands selective for each mGlu receptor have been synthesized, and pharmacological significances of these ligands have been demonstrated in animal models. Among them, mGlu2/3 receptor agonists have been proven to be effective for treating schizophrenia and anxiety disorders in clinical studies, which may prove utilities of mGlu receptor ligands for the treatment of psychiatric disorders. This article reviews recent advances in development of each mGlu receptor ligands and their therapeutic potential.
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PMID:Metabotropic glutamate receptors: potential drug targets for psychiatric disorders. 2116 Sep 8

Based on the glutamate hypothesis of schizophrenia, extensive studies to develop drugs acting on glutamate receptors have been conducted. Among glutamate receptors, metabotropic glutamate (mGlu) receptors, all of which are GPCRs, have 8 subtypes, and are involved in regulation of glutamate transmissions. Of these, much attention has been paid to mGlu2/3 receptors and mGlu5 receptor. mGlu2/3 receptor agonists improve behavioral abnormalities such as locomotor hyperactivity and cognitive deficits induced by NMDA receptor antagonists. In addition, mGlu2/3 receptor agonists attenuate glutamate overflow in the prefrontal cortex, and regulate dopamine release and 5-HT2A receptor activity, all of which have been presumed to be involved in antipsychotic actions of mGlu2/3 receptor agonists. Recently, LY2140023, an mGlu2/3 receptor agonists developed by Eli Lilly, has been demonstrated to be effective for the treatment of positive and negative symptoms of schizophrenic patients in a phase II study, while it did not cause unwanted side effects often observed with current antipsychotic medications. Moreover, a series of experiments has demonstrated that mGlu5 receptor potentiators exert antipsychotic effects in animal models of schizophrenia. Therefore, mGlu2/3 receptor and mGlu5 receptor may provide exciting targets for the development of novel medications for schizophrenia.
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PMID:[Targeting metabotropic glutamate receptors to develop novel antipsychotics]. 2122 17


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