Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP

Jesper Mosolff Mathiesen; Nannette Svendsen; Hans Bräuner-Osborne; Christian Thomsen; M Teresa Ramirez

doi:10.1038/sj.bjp.0705159

Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP

Jesper Mosolff Mathiesen, Nannette Svendsen, Hans Bräuner-Osborne, Christian Thomsen, M Teresa Ramirez

159 Citations (Scopus)

Abstract

We have identified 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) and 2-methyl-6-phenylethynyl pyridine hydrochloride (MPEP) as positive allosteric modulators for the hmGluR4. SIB-1893 and MPEP enhanced the potency and efficacy of L-2-amino-4-phophonobutyrate (L-AP4) in guanosine 5'-O-(3-[(35)S]thiotriphosphate ([(35)S]GTPgammaS) binding and efficacy in cAMP studies. These effects were fully blocked by the mGluR4 competitive antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG), indicating a dependency on receptor activation. Although SIB-1893 and MPEP had no effects alone in GTPgammaS binding, effects were observed in the cell-based cAMP assay due to media-derived activation as indicated by CPPG inhibition. Positive modulation of the mGluR4 was a receptor-specific effect since SIB-1893 and MPEP had neither effects on mGluR2-expressing cells nor on the parent BHK cell line. In [(3)H]L-AP4 binding, a two-fold decrease in K(D) but not in B(max) was observed with 100 micro M SIB-1893, whereas MPEP affected neither parameter. Finally, SIB-1893 and MPEP failed to displace [(3)H]L-AP4 binding. Taken together, these data identify positive allosteric modulators for the hmGluR4.

Original language	English
Journal	British Journal of Pharmacology
Volume	138
Issue number	6
Pages (from-to)	1026-30
ISSN	0007-1188
DOIs	https://doi.org/10.1038/sj.bjp.0705159
Publication status	Published - Mar 2003

Keywords

Allosteric Regulation
Cell Culture Techniques
Humans
Pyridines
Receptors, Glutamate
Receptors, Metabotropic Glutamate

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10.1038/sj.bjp.0705159

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title = "Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP",

abstract = "We have identified 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) and 2-methyl-6-phenylethynyl pyridine hydrochloride (MPEP) as positive allosteric modulators for the hmGluR4. SIB-1893 and MPEP enhanced the potency and efficacy of L-2-amino-4-phophonobutyrate (L-AP4) in guanosine 5'-O-(3-[(35)S]thiotriphosphate ([(35)S]GTPgammaS) binding and efficacy in cAMP studies. These effects were fully blocked by the mGluR4 competitive antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG), indicating a dependency on receptor activation. Although SIB-1893 and MPEP had no effects alone in GTPgammaS binding, effects were observed in the cell-based cAMP assay due to media-derived activation as indicated by CPPG inhibition. Positive modulation of the mGluR4 was a receptor-specific effect since SIB-1893 and MPEP had neither effects on mGluR2-expressing cells nor on the parent BHK cell line. In [(3)H]L-AP4 binding, a two-fold decrease in K(D) but not in B(max) was observed with 100 micro M SIB-1893, whereas MPEP affected neither parameter. Finally, SIB-1893 and MPEP failed to displace [(3)H]L-AP4 binding. Taken together, these data identify positive allosteric modulators for the hmGluR4.",

keywords = "Allosteric Regulation, Cell Culture Techniques, Humans, Pyridines, Receptors, Glutamate, Receptors, Metabotropic Glutamate",

author = "Mathiesen, {Jesper Mosolff} and Nannette Svendsen and Hans Br{\"a}uner-Osborne and Christian Thomsen and Ramirez, {M Teresa}",

year = "2003",

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language = "English",

volume = "138",

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T1 - Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP

AU - Mathiesen, Jesper Mosolff

AU - Svendsen, Nannette

AU - Bräuner-Osborne, Hans

AU - Thomsen, Christian

AU - Ramirez, M Teresa

PY - 2003/3

Y1 - 2003/3

N2 - We have identified 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) and 2-methyl-6-phenylethynyl pyridine hydrochloride (MPEP) as positive allosteric modulators for the hmGluR4. SIB-1893 and MPEP enhanced the potency and efficacy of L-2-amino-4-phophonobutyrate (L-AP4) in guanosine 5'-O-(3-[(35)S]thiotriphosphate ([(35)S]GTPgammaS) binding and efficacy in cAMP studies. These effects were fully blocked by the mGluR4 competitive antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG), indicating a dependency on receptor activation. Although SIB-1893 and MPEP had no effects alone in GTPgammaS binding, effects were observed in the cell-based cAMP assay due to media-derived activation as indicated by CPPG inhibition. Positive modulation of the mGluR4 was a receptor-specific effect since SIB-1893 and MPEP had neither effects on mGluR2-expressing cells nor on the parent BHK cell line. In [(3)H]L-AP4 binding, a two-fold decrease in K(D) but not in B(max) was observed with 100 micro M SIB-1893, whereas MPEP affected neither parameter. Finally, SIB-1893 and MPEP failed to displace [(3)H]L-AP4 binding. Taken together, these data identify positive allosteric modulators for the hmGluR4.

AB - We have identified 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893) and 2-methyl-6-phenylethynyl pyridine hydrochloride (MPEP) as positive allosteric modulators for the hmGluR4. SIB-1893 and MPEP enhanced the potency and efficacy of L-2-amino-4-phophonobutyrate (L-AP4) in guanosine 5'-O-(3-[(35)S]thiotriphosphate ([(35)S]GTPgammaS) binding and efficacy in cAMP studies. These effects were fully blocked by the mGluR4 competitive antagonist (RS)-alpha-cyclopropyl-4-phosphonophenylglycine (CPPG), indicating a dependency on receptor activation. Although SIB-1893 and MPEP had no effects alone in GTPgammaS binding, effects were observed in the cell-based cAMP assay due to media-derived activation as indicated by CPPG inhibition. Positive modulation of the mGluR4 was a receptor-specific effect since SIB-1893 and MPEP had neither effects on mGluR2-expressing cells nor on the parent BHK cell line. In [(3)H]L-AP4 binding, a two-fold decrease in K(D) but not in B(max) was observed with 100 micro M SIB-1893, whereas MPEP affected neither parameter. Finally, SIB-1893 and MPEP failed to displace [(3)H]L-AP4 binding. Taken together, these data identify positive allosteric modulators for the hmGluR4.

KW - Allosteric Regulation

KW - Cell Culture Techniques

KW - Humans

KW - Pyridines

KW - Receptors, Glutamate

KW - Receptors, Metabotropic Glutamate

U2 - 10.1038/sj.bjp.0705159

DO - 10.1038/sj.bjp.0705159

M3 - Journal article

C2 - 12684257

SN - 0007-1188

VL - 138

SP - 1026

EP - 1030

JO - British Journal of Pharmacology

JF - British Journal of Pharmacology

IS - 6

ER -

Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP

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Keywords

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