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Journal of Neuroscience, Vol 14, 3370-3377, Copyright © 1994 by Society for Neuroscience
Analysis of agonist and antagonist activities of phenylglycine derivatives for different cloned metabotropic glutamate receptor subtypes
Y Hayashi, N Sekiyama, S Nakanishi, DE Jane, DC Sunter, EF Birse, PM Udvarhelyi and JC Watkins
Institute for Immunology, Kyoto University Faculty of Medicine, Japan.
The metabotropic glutamate receptors (mGluRs) consist of at least seven
different subtypes and are coupled to intracellular signal transduction via
G proteins. However, the lack of specific antagonists for the mGluRs
limited the precise characterization of the role of the individual mGluRs.
In this study, we investigated the agonist and antagonist activities of a
series of phenylglycine derivatives for the mGluRs by examining their
effects on the signal transduction of representative mGluR1, mGluR2, and
mGluR4 subtypes expressed individually in Chinese hamster ovary cells. The
phenylglycine derivatives examined included (S)- and (R)-forms of 3-
hydroxyphenylglycine (3HPG), 4-carboxy-phenylglycine (4CPG), 4-carboxy-
3-hydroxyphenylglycine (4C3HPG), 3-carboxy-4-hydroxyphenylglycine (3C4HPG),
and (+)- and (-)-alpha-methyl-4-carboxyphenylglycine (alpha M4CPG). Among
these 10 compounds, (S)-3HPG acted as an agonist for mGluR1, while
(S)-4C3HPG, (S)-3C4HPG, and (S)-4CPG served as effective agonists for
mGluR2. The rank order of agonist potencies for mGluR2 was L-glutamate >
(S)-4C3HPG > (S)-3C4HPG > (S)-4CPG. No other phenylglycine
derivatives showed any definite agonist activity on either mGluR1 or
mGluR2. Among the phenylglycine derivatives with no mGluR1 agonist
activity, (S)-4C3HPG, (S)-3C4HPG, (S)-4CPG, and (+)- alpha M4CPG
effectively antagonized the action of L-glutamate on mGluR1. The rank order
of antagonist potencies was (S)-4C3HPG > or = (S)-4CPG > or =
(+)-alpha M4CPG > (S)-3C4HPG. The Schild plot analysis indicated that
(RS)-4C3HPG, (S)-4CPG, and (+)-alpha M4CPG all act as competitive
antagonists for mGluR1 with pA2 values of 4.38, 4.46, and 4.38,
respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
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