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mGluR Metabotropic glutamate receptors mGluR (metabotropic glutamate receptor) is a type of glutamate receptor that are active through an indirect metabotropic process. They are members of thegroup C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatoryneurotransmitter. The mGluRs perform a variety of functions in the central and peripheral nervous systems: mGluRs are involved in learning, memory, anxiety, and the perception of pain. mGluRs are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues. Eight different types of mGluRs, labeled mGluR1 to mGluR8, are divided into groups I, II, and III. Receptor types are grouped based on receptor structure and physiological activity. www.MedChemExpress.com 1 mGluR Inhibitors & Modulators (1R,2S)-VU0155041 (R)-ADX-47273 Cat. No.: HY-14417A Cat. No.: HY-13058B Bioactivity: (1R,2S)-VU0155041, Cis regioisomer of VU0155041, is a partial Bioactivity: (R)-ADX-47273 is a potent mGluR5 positive allosteric mGluR4 agonist with an EC of 2.35 μM. 50 modulator, with an EC50 of 168 nM for potentiation . Purity: 98.42% Purity: 99.25% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 5 mg, 10 mg, 25 mg 5 mg, 10 mg, 50 mg (RS)-MCPG (S)-MCPG (alpha-MCPG) Cat. No.: HY-100371 ((+)-MCPG) Cat. No.: HY-100406 Bioactivity: (RS)-MCPG is a non-selective group I/group II metabotropic Bioactivity: (S)-MCPG is the active isomer of (RS)-MCPG (Cat. No. glutamate receptor antagonist. HY-100371), non-selective group I/group II metabotropic glutamate receptor antagonist. In vivo: (S)-MCPG (20.8 μg) injected intraventricularly (i.c.v.) before testing impaired the performance of rats in the spatial version of the Morris… Purity: 98.0% Purity: 98.10% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg 5 mg, 10 mg, 25 mg, 50 mg ADX-47273 ADX88178 Cat. No.: HY-13058 Cat. No.: HY-18654 Bioactivity: ADX-47273 is a positive allosteric modulator selective for the Bioactivity: ADX88178 is a potent positive allosteric modulator for metabotropic glutamate receptor subtype mGluR5(EC50=170 nM). metabotropic glutamate receptor 4 ( mGluR4) with EC50 of IC50 value: 170 nM(EC50) [1] [2] Target: positive allosteric 4 nM for human mGluR4. modulator (PAM) of mGluR5 in vitro: ADX-47273 increased (9-fold) the response to threshold concentration of glutamate… Purity: 99.34% Purity: 98.59% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 5 mg, 10 mg, 50 mg, 100 mg 1 mg, 5 mg, 10 mg, 50 mg, 100 mg AZD 9272 AZD-8529 Cat. No.: HY-110254 Cat. No.: HY-107457 Bioactivity: AZD 9272 is a brain penetrant mGluR5 antagonist. Bioactivity: AZD-8529 is a potent, highly selective and orally bioavailable positive allosteric modulator of mGluR2, with an EC50 of 285 nM, and shows no positive allosteric modulator responses at 20-25 M on the mGluR1, 3, 4, 5, 6, 7, and 8 subtypes. Purity: >98% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 5 mg, 10 mg, 25 mg Size: 250 mg, 500 mg Basimglurant BMT-145027 (RG7090; CTEP Derivative) Cat. No.: HY-15446 Cat. No.: HY-100728 Bioactivity: Basimglurant (RG7090) is a potent, selective and orally Bioactivity: BMT-145027 is an mGluR5 positive allosteric modulator available mGlu5 negative allosteric modulator with a Kd without inherent agonist activity, exhibits an EC50 of 47 of 1.1 nM. nM. Purity: 99.56% Purity: 98.0% Clinical Data: Phase 1 Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 5 mg, 10 mg, 50 mg, 100 mg 1 mg, 5 mg, 10 mg, 50 mg, 100 mg 2 Tel: 609-228-6898 Fax: 609-228-5909 Email: [email protected] CFMTI CPPHA Cat. No.: HY-100402 Cat. No.: HY-14612 Bioactivity: CFMTI is a potent and selective metabotropic glutamate Bioactivity: CPPHA is a selective positive allosteric modulator of mGluR5 receptor (mGluR) 1 allosteric antagonist with IC50 of 2.6 nM. receptor. The selectivity of CFMTI to mGluR1 over mGluR5 was >2000-fold. target : mGluR IC 50: 2.6 nM In vitro: The IC50 values of CFMTI against human mGluR5 were 5400 ± 1200 nM,… Purity: 98.0% Purity: 97.93% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 1 mg, 5 mg, 10 mg, 25 mg, 50 mg 5 mg, 10 mg, 50 mg CTEP DFMTI (RO 4956371; mGluR5 inhibitor) Cat. No.: HY-15445 (MK5435) Cat. No.: HY-100404 Bioactivity: CTEP (RO 4956371) is a novel, long-acting, orally bioavailable Bioactivity: DFMTI can completely block the rmGlu1 L757V glutamate allosteric antagonist of mGlu5 receptor response. with IC50 of 2.2 nM, and shows > 1000-fold selectivity over other mGlu receptors. Purity: 97.49% Purity: 99.25% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 5 mg, 10 mg, 50 mg, 100 mg 1 mg, 5 mg, 10 mg, 50 mg, 100 mg Dipraglurant E4CPG (ADX48621) Cat. No.: HY-14859 Cat. No.: HY-100372 Bioactivity: Dipraglurant (ADX 48621) is a mGluR5 antagonists with IC50 of Bioactivity: E4CPG is a novel group I/group II metabotropic glutamate 0.021 μM. receptor antagonist, more potent than (RS)-MCPG . Purity: 99.99% Purity: 98.0% Clinical Data: Phase 2 Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 5 mg, 10 mg, 25 mg, 50 mg, 100 mg 1 mg, 5 mg, 10 mg, 50 mg Eglumegad FITM (LY354740; Eglumetad) Cat. No.: HY-18941 Cat. No.: HY-101845 Bioactivity: Eglumegad (LY354740) is a highly potent and selective group Bioactivity: FITM is a negative allosteric modulator of mGlu1 receptor II (mGlu2/3) receptor agonist with IC50s of 5 and 24 nM on with a Ki of 2.5 nM. transfected human mGlu2 and mGlu3 receptors, respectively. Purity: 98.0% Purity: 98.82% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 5 mg, 10 mg, 50 mg Size: 10mM x 1mL in DMSO, 2 mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg Foliglurax monohydrochloride FPTQ (PXT002331 (monohydrochloride)) Cat. No.: HY-108703A Cat. No.: HY-100382 Bioactivity: Foliglurax monohydrochloride (PXT002331 monohydrochloride) is Bioactivity: FPTQ is mGluR1 antagonist with IC50 of 6 nM and 1.4 nM for a highly selective and potent, brain-penetrant mGluR4 human and mouse mGluR1 respectively. Inhibit [3H] FTIDC positive allosteric modulator (PAM), with an EC50 of 79±19 target: mGluR1 IC 50: 6 nM [1] In vivo: FPTQ exhibited dose-dependent and plasma concentration- dependent receptor nM [1]. Antiparkinsonian effect [1]. occupancy in the cerebellum and striatum. Compound A inhibit… Purity: 98.93% Purity: 99.89% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg 1 mg, 5 mg, 10 mg, 25 mg, 50 mg www.MedChemExpress.com 3 JNJ-40411813 JNJ-42153605 (ADX-71149) Cat. No.: HY-15748 Cat. No.: HY-18162 Bioactivity: JNJ-40411813 is a novel positive allosteric modulator of the Bioactivity: JNJ-42153605 is a positive allosteric modulator of the metabotropic Glutamate 2 receptor (mGlu2R) with EC50 of 147 metabotropic glutamate 2 ( mGlu2) receptor with an EC50 nM. IC50 value: 147 nM(EC50) Target: mGlu2R JNJ-40411813 of 17 nM. displayed an optimal interplay between potency, selectivity, favorable ADMET/PK and cardiovascular safety profile, and… Purity: 99.69% Purity: 98.10% Clinical Data: Phase 2 Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 1 mg, 5 mg, 10 mg, 50 mg, 100 mg 5 mg, 10 mg, 50 mg, 100 mg JNJ-46778212 JNJ16259685 (VU 0409551) Cat. No.: HY-19559 Cat. No.: HY-100407 Bioactivity: JNJ-46778212 (VU 0409551) is an mGlu5 positive allosteric Bioactivity: JNJ16259685 is a selective antagonist of mGlu1 receptor, modulator with an EC50 of 260 nM. and inhibits the synaptic activation of mGlu1 in a concentration-dependent manner with IC50 of 19 nM. Purity: 99.24% Purity: 98.85% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 10mM x 1mL in DMSO, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg 5 mg, 10 mg, 25 mg, 50 mg L-APB L-Cysteinesulfinic acid (L-AP 4) Cat. No.: HY-100781A Cat. No.: HY-100804 Bioactivity: L-APB is a potent and specific agonist for the group III Bioactivity: L-Cysteinesulfinic acid is a potent agonist at several rat metabotropic glutamate receptors ( mGluRs) with pEC s of mGluRs, with EC50s of 0.13, 0.29, 1.0, 249 μM for mGlu 50 3.92±0.03, 4.6±0.2, 3.9±0.2, 2.7±0.2, 4.0±0.2, and 3.94±0.08 4, mGlu 8, mGlu 6 and mGlu 7 receptors, respectively. for mGluR1, mGluR5, mGluR2, mGluR4, mGluR6, and mGluR8, respectively. Purity: 99.0% Purity: >98% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10mM x 1mL in DMSO, Size: 250 mg, 500 mg 1 mg, 5 mg L-Glutamine Lu AF21934 (L-Glutamic acid 5-amide) Cat.
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  • Diamandis Thesis

    Diamandis Thesis

    !"!#$ CHEMICAL GENETIC INTERROGATION OF NEURAL STEM CELLS: PHENOTYPE AND FUNCTION OF NEUROTRANSMITTER PATHWAYS IN NORMAL AND BRAIN TUMOUR INITIATING NEURAL PRECUSOR CELLS by Phedias Diamandis A thesis submitted in conformity with the requirements for the degree of Doctor of Philosophy. Department of Molecular Genetics University of Toronto © Copyright by Phedias Diamandis 2010 Phenotype and Function of Neurotransmitter Pathways in Normal and Brain Tumor Initiating Neural Precursor Cells Phedias Diamandis Doctor of Philosophy Department of Molecular Genetics University of Toronto 2010 &'(!)&*!% The identification of self-renewing and multipotent neural stem cells (NSCs) in the mammalian brain brings promise for the treatment of neurological diseases and has yielded new insight into brain cancer. The complete repertoire of signaling pathways that governs these cells however remains largely uncharacterized. This thesis describes how chemical genetic approaches can be used to probe and better define the operational circuitry of the NSC. I describe the development of a small molecule chemical genetic screen of NSCs that uncovered an unappreciated precursor role of a number of neurotransmitter pathways commonly thought to operate primarily in the mature central nervous system (CNS). Given the similarities between stem cells and cancer, I then translated this knowledge to demonstrate that these neurotransmitter regulatory effects are also conserved within cultures of cancer stem cells. I then provide experimental and epidemiologically support for this hypothesis and suggest that neurotransmitter signals may also regulate the expansion of precursor cells that drive tumor growth in the brain. Specifically, I first evaluate the effects of neurochemicals in mouse models of brain tumors. I then outline a retrospective meta-analysis of brain tumor incidence rates in psychiatric patients presumed to be chronically taking neuromodulators similar to those identified in the initial screen.