Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP.
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.
Mathiesen
Jesper Mosolff
JM
Division of Biological Research, Department of Molecular Pharmacology, H. Lundbeck A/S, DK-2500 Valby, Denmark.
Svendsen
Nannette
N
Bräuner-Osborne
Hans
H
Thomsen
Christian
C
Ramirez
M Teresa
MT
D000494:Allosteric Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D018929:Cell Culture Techniques; D006801:Humans; D011725:Pyridines / Q000494:pharmacology*; D017470:Receptors, Glutamate / Q000187:drug effects*; D018094:Receptors, Metabotropic Glutamate / Q000187:drug effects
D011725:Pyridines; D017470:Receptors, Glutamate; D018094:Receptors, Metabotropic Glutamate; C120148:SIB 1893; C121465:6-methyl-2-(phenylethynyl)pyridine; C108823:metabotropic glutamate receptor 4