New phenylglycine derivatives with potent and selective antagonist activity at presynaptic glutamate receptors in neonatal rat spinal cord

Jane, David E.; Pittaway, K.; Sunter, David; Thomas, Nicola; Watkins, Johnathan

doi:10.1016/0028-3908(95)00063-c

Cited by 102 publications

(40 citation statements)

References 25 publications

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“…Second, group I antagonists UPF523 (Pellicciari et al, 1995;Sacaan et al, 1996) and MCPG attenuate rotation induced by 1S,3R-ACPD or DHPG. The Group II / III antagonists MTPG and MPPG (Jane et al, 1995;Beddingfield et al, 1996) have no effect, even at higher doses, although they are more potent at their respective receptors than UPF523 and MCPG are at group I receptors (Jane et al, 1995;Pellicciari et al, 1995;Beddingfield et al, 1996). Additionally, chronic lithium treatment, which impairs mGluRmediated PI signaling, suppresses 1S,3R-ACPD-induced rotational behavior (K. Kaatz and R. Albin, unpublished observations).…”

Section: Discussion Pharmacologymentioning

confidence: 99%

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

1997

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Metabotropic glutamate receptors (mGluRs) are a major class of excitatory amino acid receptors. Eight mGluR subtypes, coupled to a variety of effector systems, have been cloned. These receptors have been classified into three groups based on amino acid sequence homology, effector systems, and pharmacological profile. Group I mGluRs increase phosphoinositide turnover, whereas groups II and III mGluRs are negatively coupled to adenylyl cyclase. The striatum possesses a high density of mGluR binding sites, and several mGluR mRNAs and proteins are expressed by striatal neurons. In rats, unilateral striatal injection of the nonsubtype selective mGluR agonist 1-aminocyclopentane-1S,3R-dicarboxylic acid (1S,3R-ACPD) results in contralateral rotation with delayed onset, thought to be secondary to an increase in dopamine release. We sought to determine the mGluR subtype(s) involved, the modulation of the rotation by other basal ganglia neurotransmitter systems, and the functional anatomy underlying the rotational behavior. The group I mGluR agonist 3,5-dihydroxyphenylglycine (DHPG) induced contralateral rotation in a dose-dependent manner, whereas group II and group III agonists were ineffective. Rotation induced by DHPG or 1S,3R-ACPD was attenuated by group I antagonists, but not by group II or group III antagonists. This suggests that the rotation is mediated by group I mGluRs. Rotation induced by DHPG or 1S,3R-ACPD was attenuated by pretreatment with antagonists at muscarinic cholinergic, adenosine A 2 , dopamine D 2 , or dopamine D 1 receptors. Examination of FOS-like immunoreactivity after group I and group II mGluR agonist administration suggests increased activity in the striatopallidal pathway. However, [ 14 C]-2-deoxyglucose uptake studies indicate increased activity in nuclei of the striatopallidal (indirect) pathway, particularly in the subthalamic nucleus, only after group I mGluR activation. Key words: metabotropic glutamate receptor; basal ganglia; subthalamic nucleus; striatum; dopamine; adenosine A2 receptors; muscarinic receptorsExcitatory amino acids (EAAs) are important neurotransmitters in the basal ganglia, and EAAergic agents are being investigated actively as possible pharmacotherapies for basal ganglia disorders. A major class of EAA receptors are the metabotropic glutamate receptors (mGluRs), coupled to second messenger systems via G-proteins. Eight mGluR subtypes have been cloned, several of which possess splice variants. These mGluR subtypes have been categorized into three groups based on their amino acid sequence homology, effector systems, and pharmacological profile. When expressed and activated in transfection systems, group I receptors (mGluRs 1 and 5) stimulate phosphoinositide hydrolysis. Group II (mGluRs 2 and 3) and group III (mGluRs 4 -8) receptors inhibit adenylyl cyclase, although with different pharmacological profiles (for review, see Pin and Duvosin, 1995;Roberts, 1995). Ligand-binding studies have shown the striatum to possess a high density of mGluR binding sites (Albin et al....

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Section: Discussion Pharmacologymentioning

confidence: 99%

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

1997

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“…Surprisingly, CPPG (300 M), known as a group III mGluR antagonist (Jane et al, 1996;von Gersdorff et al, 1997;Awatramani and Slaughter, 2001;Nawy, 2004), could not suppress the inhibitory effect of L-AP-4 (20 -200 M) on the cone I Ca (n ϭ 4). MPPG (300 M), another group III mGluR antagonist (Jane et al, 1995;Koulen et al, 1999), was also ineffective in antagonizing L-AP-4-induced outward current in ON bipolar cells of the newt retina (data not shown). Group III mGluRs in newt retinas seem to have different pharmacological characteristics.…”

Section: L-ap-4 Inhibited L-type I Ca In Conesmentioning

confidence: 96%

Group III Metabotropic Glutamate Receptors and Exocytosed Protons Inhibit L-Type Calcium Currents in Cones But Not in Rods

Hosoi¹,

Arai²,

Tachibana³

2005

J. Neurosci.

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“…In some of these cases, however, the activity of a compound at each of the cloned group III receptors has not been directly compared using the same assay system. In fact, for the compound MSPG, there is no information available for the activity of this ligand at any of the cloned group III mGluRs, and the ability of the compound to act as a group III mGluR antagonist has been inferred from its ability to block L-AP4 responses in various neuronal preparations (Jane et al, 1995;Bedingfield et al, 1996). Generation of the cell lines described above allowed us to rapidly assess the antagonist activity of a number of commercially available ligands described as group III mGluR antagonists.…”

Section: Mglur-mediated Thallium Flux Through Girk Channels 1215mentioning

confidence: 99%

A Novel Assay of G_i/o-Linked G Protein-Coupled Receptor Coupling to Potassium Channels Provides New Insights into the Pharmacology of the Group III Metabotropic Glutamate Receptors

Niswender¹,

Johnson²,

Luo³

et al. 2008

Mol Pharmacol

103

145

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The group III metabotropic glutamate receptors (mGluRs) represent a family of presynaptically expressed G-protein-coupled receptors (GPCRs) with enormous therapeutic potential; however, robust cellular assays to study their function have been difficult to develop. We present here a new assay, compatible with traditional high-throughput screening platforms, to detect activity of pharmacological ligands interacting with G i/o -coupled GPCRs, including the group III mGluRs 4, 7, and 8. The assay takes advantage of the ability of the G␤␥ subunits of G i and G o heterotrimers to interact with G-protein regulated inwardly rectifying potassium channels (GIRKs), and we show here that we are able to detect the activity of multiple types of pharmacophores including agonists, antagonists, and allosteric modulators of several distinct GPCRs. Using GIRK-mediated thallium flux, we perform a side-by-side comparison of the activity of a number of commercially available compounds, some of which have not been extensively evaluated because of the previous lack of robust assays at each of the three major group III mGluRs. It is noteworthy that several compounds previously considered to be general group III mGluR antagonists have very weak activity using this assay, suggesting the possibility that these compounds may not effectively inhibit these receptors in native systems. We anticipate that the GIRKmediated thallium flux strategy will provide a novel tool to advance the study of G i/o -coupled GPCR biology and promote ligand discovery and characterization.The metabotropic glutamate receptors (mGluRs) are among the most abundantly expressed receptors in the mammalian central nervous system and are thought to play critical roles in regulating activity in a broad range of CNS circuits (Conn and Pin, 1997). Despite an increasing appreciation of the involvement of mGluRs in CNS function, however, progress in understanding the signaling pathways and functional properties of some members of the mGluR family has been relatively slow. This is especially true for the group III mGluRs, which include mGluRs 4, 6, 7, and 8.

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New phenylglycine derivatives with potent and selective antagonist activity at presynaptic glutamate receptors in neonatal rat spinal cord

Cited by 102 publications

References 25 publications

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

Group III Metabotropic Glutamate Receptors and Exocytosed Protons Inhibit L-Type Calcium Currents in Cones But Not in Rods

A Novel Assay of G_i/o-Linked G Protein-Coupled Receptor Coupling to Potassium Channels Provides New Insights into the Pharmacology of the Group III Metabotropic Glutamate Receptors

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New phenylglycine derivatives with potent and selective antagonist activity at presynaptic glutamate receptors in neonatal rat spinal cord

Cited by 102 publications

References 25 publications

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [14C]-2-Deoxyglucose Autoradiographic Study

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [14C]-2-Deoxyglucose Autoradiographic Study

Group III Metabotropic Glutamate Receptors and Exocytosed Protons Inhibit L-Type Calcium Currents in Cones But Not in Rods

A Novel Assay of Gi/o-Linked G Protein-Coupled Receptor Coupling to Potassium Channels Provides New Insights into the Pharmacology of the Group III Metabotropic Glutamate Receptors

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Product

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Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

Metabotropic Glutamate Agonist-Induced Rotation: A Pharmacological, FOS Immunohistochemical, and [¹⁴C]-2-Deoxyglucose Autoradiographic Study

A Novel Assay of G_i/o-Linked G Protein-Coupled Receptor Coupling to Potassium Channels Provides New Insights into the Pharmacology of the Group III Metabotropic Glutamate Receptors