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Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB‐1893 and MPEP
Author(s) -
Mathiesen Jesper Mosolff,
Svendsen Nannette,
BräunerOsborne Hans,
Thomsen Christian,
Ramirez M Teresa
Publication year - 2003
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1038/sj.bjp.0705159
Subject(s) - gtpgammas , allosteric regulation , chemistry , metabotropic glutamate receptor 2 , metabotropic glutamate receptor 4 , metabotropic glutamate receptor 5 , metabotropic glutamate receptor , metabotropic receptor , stereochemistry , pharmacology , receptor , biochemistry , glutamate receptor , biology , agonist
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]GTPγS) binding and efficacy in cAMP studies. These effects were fully blocked by the mGluR4 competitive antagonist (RS)‐α‐cyclopropyl‐4‐phosphonophenylglycine (CPPG), indicating a dependency on receptor activation. Although SIB‐1893 and MPEP had no effects alone in GTPγS 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 μ 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. British Journal of Pharmacology (2003) 138 , 1026–1030. doi: 10.1038/sj.bjp.0705159