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)

(+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (4, LY354740), a highly selective and orally active group II metabotropic glutamate receptor (mGluR) agonist, has increased interest in the study of group II mGluRs. Our interest focused on a conformationally constrained form of compound 4, because it appeared that the rigid form resulted in not only selectivity for group II mGluR but was orally active. Therefore, we introduced a fluorine atom to compound 4, based on the molecular size (close resemblance to hydrogen atom) and electronegativity (effects on the electron distribution in the molecule) of this atom and carbon-fluorine bond energy. Compound (+)-7 (MGS0008), the best compound among 3-fluoro derivatives 7-10, retained the agonist activity of compound 4 for mGluR2 and mGluR3 ((+)-7: EC(50) = 29.4 +/- 3.3 nM and 45.4 +/- 8.4 nM for mGluR2 and mGluR3, respectively; 4: EC(50) = 18.3 +/- 1.6 nM and 62.8 +/- 12 nM for mGluR2 and mGluR3, respectively) and increased the oral activity of compound 4 ((+)-7: ED(50) = 5.1 mg/kg and 0.26 mg/kg for phencyclidine (PCP)-induced hyperactivity and PCP-induced head-weaving behavior, respectively; 4: ED(50) = >100 mg/kg and 3.0 mg/kg for PCP-induced hyperactivity and PCP-induced head-weaving behavior, respectively). In addition, a compound [(3)H]-(+)-7 binding study using mGluR2 or 3 expressed in CHO cells was successful ((+)-7: K(i) = 47.7 +/- 17 nM and 65.9 +/- 7.1 nM for mGluR2 and mGluR3, respectively; 4: K(i) = 23.4 +/- 7.1 nM and 53.5 +/- 13 nM for mGluR2 and mGluR3, respectively). On the basis of a successful result of compound 7, we focused on the introduction of a fluorine atom on the C6 position of compound 4. (1R,2S,5R, 6R)-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid ((-)-11) exhibited a high degree of agonist activity for group II mGluRs equal to that of compound 4 or 7 ((-)-11: K(i) = 16.6 +/- 5.6 and 80.9 +/- 31 nM for mGluR2 and mGluR3, respectively). Our interest shifted to modification on CH(2) at C4 position of compound 11, since replacement of the CH(2) group with either an oxygen atom or sulfur atom yielded compound 5 or 6, resulting in increased agonist activity. We selected a carbonyl group instead of CH(2) at the C4 position of compound 11. The carbonyl group might slightly change the relative conformation of three functional groups, the amino group and two carboxylic acids, which have important roles in mediating the interaction between group II mGluRs and their ligand, compared with the CH(2) group of 4, oxygen atom of 5, and sulfur atom of 6. (1R,2S,5S,6S)-2-Amino-6-fluoro-4-oxobicyclo[3.1. 0]hexane-2,6-dicarboxylic acid monohydrate ((+)-14, MGS0028) exhibited a remarkably high degree of agonist activity for mGluR2 (K(i) = 0.570 +/- 0.10 nM) and mGluR3 (K(i) = 2.07 +/- 0.40 nM) expressed in CHO cells but not mGluR4, 6, 7, 1a, or 5 expressed in CHO cells (K(i) = >100 000 nM). Furthermore, compound (+)-14 strongly inhibited phencyclidine (PCP)-induced head-weaving behavior (ED(50) = 0.090 microg/kg) and hyperactivity (ED(50) = 0.30 mg/kg) in rats. Thus, (+)-7 and (+)-14 are potent, selective, and orally active group II mGluR agonists and might be useful not only for exploring the functions of mGluRs but in the treatment of schizophrenia.
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PMID:Synthesis, SARs, and pharmacological characterization of 2-amino-3 or 6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent, selective, and orally active group II metabotropic glutamate receptor agonists. 1112 99

Disturbances in glutamate function have been implicated in the pathophysiology of schizophrenia. We searched for mutations in the exons of the metabotropic glutamate receptor mGluR4 (GRM4) gene on human chromosome 6p21.3 and evaluated associations between these polymorphisms with schizophrenia in Japanese patients. Nine nuclear variants of 450G > T, 1455T > C, 2202A > G, 2389G > A (Val797 > Ile797), 2890A > G, 3601C > T, 3639C > T, IVS4-36G > A, and IVS5 + 29(CCGGG)1-2, were found. The Val797Ile variant, although found in both the patient and control groups, was rare and the only variant that causes a non-synonymous amino acid change. There was no statistically significant association between any mGluR4 gene polymorphism and schizophrenia. Thus, this study did not provide evidence for the contribution of the mGluR4 gene to schizophrenia in the Japanese.
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PMID:Mutation screening of the metabotropic glutamate receptor mGluR4 (GRM4) gene in patients with schizophrenia. 1152 21

Moderate hyperhomocysteinemia is associated with several diseases, including coronary artery disease, stroke, Alzheimer's disease, schizophrenia, and spina bifida. However, the mechanisms for their pathogenesis are unknown but could involve the interaction of homocysteine or its metabolites with molecular targets such as neurotransmitter receptors, channels, or transporters. We discovered that L-homocysteine sulfinic acid (L-HCSA), L-homocysteic acid, L-cysteine sulfinic acid, and L-cysteic acid are potent and effective agonists at several rat metabotropic glutamate receptors (mGluRs). These acidic homocysteine derivatives 1) stimulated phosphoinositide hydrolysis in the cells stably expressing the mGluR1, mGluR5, or mGluR8 (plus Galpha(qi9)) and 2) inhibited the forskolin-induced cAMP accumulation in the cells stably expressing mGluR2, mGluR4, or mGluR6, with different potencies and efficacies depending on receptor subtypes. Of the four compounds, L-HCSA is the most potent agonist at mGluR1, mGluR2, mGluR4, mGluR5, mGluR6, and mGluR8. The effects of the four agonists were selective for mGluRs because activity was not discovered when L-HCSA and several other homocysteine derivatives were screened against a large panel of cloned neurotransmitter receptors, channels, and transporters. These findings imply that mGluRs are candidate G-protein-coupled receptors for mediating the intracellular signaling events induced by acidic homocysteine derivatives. The relevance of these findings for the role of mGluRs in the pathogenesis of homocysteine-mediated phenomena is discussed.
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PMID:L-homocysteine sulfinic acid and other acidic homocysteine derivatives are potent and selective metabotropic glutamate receptor agonists. 1264 61

The glutamatergic dysfunction has been implicated in pathophysiology of schizophrenia. The Group III metabotropic glutamate receptor 4 (mGluR4), 6, 7, and 8 are thought to modulate glutamatergic transmission in the brain by inhibiting glutamate release at the synapse. We tested association of schizophrenia with GRM8 using 22 single nucleofide polymorphisms (SNPs) with the average intervals of 40.3 kb in the GRM8 region in 100 case-control pairs for the SNPs. Although we observed significant associations of schizophrenia with two SNPs, SNP18 (rs2237748, allele: P = 0.0279; genotype: P = 0.0124) and SNP19 (rs2299472, allele: P = 0.0302; genotype: P = 0.0127), none of two SNPs showed significant association with disease after Bonferroni correction. Both SNP18 and SNP19 were included in a large region (>330 kb) in which SNPs are in linkage disequilibrium (LD) at the 3' region of GRM8. We also tested haplotype association of schizophrenia with constructed haplotypes of the SNPs in LD. Significant associations were detected for the combinations of SNP5-SNP6 (chi(2) = 18.12, df = 3, P = 0.0004, P corr = 0.0924 with Bonferroni correction), SNP4-SNP5-SNP6 (chi(2) = 27.50, df = 7, P = 0.0075, P corr = 0.015 with Bonferroni correction), and SNP5-SNP6-SNP7 (chi(2) = 23.92, df = 7, P = 0.0011, P corr = 0.0022 with Bonferroni correction). Thus, we conclude that at least one susceptibility locus for schizophrenia is located within the GRM8 region in Japanese.
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PMID:Positive associations of polymorphisms in the metabotropic glutamate receptor type 8 gene (GRM8) with schizophrenia. 1521 21

Positive allosteric modulators of metabotropic glutamate receptors (mGluRs) are the subject of intensive research due to their emerging therapeutic potential for a range of psychiatric and neurological disorders such as pain, anxiety, cognition, Parkinson's disease and schizophrenia. Positive allosteric modulators, which are small molecules capable of enhancing agonist-mediated receptor activity while possessing no intrinsic agonist activity, have recently been described for group I (mGluR1 and mGluR5), group II (mGluR2) and group III (mGluR4) mGluRs. Relative to classical mGluR agonists, these molecules offer improved selectivity versus other mGluRs and chemical tractability, and may reduce the liability of receptor desensitization.
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PMID:Recent advances in positive allosteric modulators of metabotropic glutamate receptors. 1602 81

Although much information about metabotropic glutamate receptors (mGluRs) and their role in normal and pathologic brain function has been accumulated during the last decades, the role of group III mGluRs is still scarcely documented. Here, we examined mGluR4 knockout mice for types of behavior and synaptic plasticity that depend on either the hippocampus or the prefrontal cortex (PFC). We found improved spatial short- and long-term memory in the radial arm maze, which was accompanied by enhanced long-term potentiation (LTP) in hippocampal CA1 region. In contrast, LTP in the PFC was unchanged when compared with wild-type controls. Changes in paired-pulse facilitation that became overt in the presence of the GABAA antagonist picrotoxin indicated a function of mGluR4 in maintaining the excitation/inhibition balance, which is of crucial importance for information processing in the brain and the deterioration of these processes in neuropsychological disorders such as autism, epilepsy and schizophrenia.
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PMID:Improved spatial learning is associated with increased hippocampal but not prefrontal long-term potentiation in mGluR4 knockout mice. 2371 30

Metabotropic glutamate receptors (mGluRs) belong to class C G-protein-coupled receptors. They are expressed throughout the nervous system on both neurons and glial cells. In the central nervous system (CNS), mGluRs are mainly located in the proximity of the synaptic cleft where they regulate glutamatergic transmission in addition to a number of other neurotransmitters. To date, eight subtypes of mGluRs (mGluR1-mGluR8) have been cloned and classified into three groups on the basis of sequence similarities, and pharmacological and biochemical properties. Consequently, group I mGluRs includes mGluR1 and mGluR5, group II mGluRs includes mGluR2 and mGluR3, and group III mGluRs consists of mGluR4, mGluR6, mGluR7, and mGluR8. With the exception of mGluR6, whose localization is restricted within the retina, all mGluRs are ubiquitously expressed throughout the peripheral and CNS with some subtype specificity in different anatomical regions. mGluRs participate in many physiological processes and play important roles in a number of neurological conditions including anxiety, depression, schizophrenia, and neurodegenerative disorders. mGluRs also participate in the physiological transmission of pain stimuli as well as to mechanisms involved in the establishment of chronic pain. Therefore, these receptors are attractive targets for therapeutic intervention in several neurological disorders including chronic pain. Thus, understanding the physiological function and role of each mGluR subtype in the development of chronic pain will provide a better insight into the potential use of subtype-selective drugs currently being developed as orthosteric or allosteric ligands.
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PMID:Modulation of Chronic Pain by Metabotropic Glutamate Receptors. 2692 9