Analysis of agonist and antagonist activities of phenylglycine derivatives for different cloned metabotropic glutamate receptor subtypes

Abstract

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)

Structural views of the ligand-binding cores of a metabotropic glutamate receptor complexed with an antagonist and both glutamate and Gd 3+

“…Its derivative, S-MCPG, is a nonselective antagonist for group I and II receptors (5-7), whereas it has little or no activity with group III receptors (6,22). All of the residues that directly recognize the antagonist are completely conserved among all of the groups, except for Y74.…”

“…To obtain clearer insights into the structural basis of receptor activation, we have determined the crystal structure of m1-LBR complexed with an antagonist, (S)-(␣)-methyl-4-carboxyphenylglycine (S-MCPG) (5)(6)(7). Furthermore, we have solved the crystal structure in the presence of both the native agonist, L-glutamate, and gadolinium ions, because metal cations, including Gd 3ϩ , modulate the signaling of mGluRs (8)(9)(10)(11).…”

Role of Group III Metabotropic Glutamate Receptors in Excitotoxin‐Induced Cerebellar Granule Cell Death

“…That MSOP inhibited ACPD-induced death to a similar level as MCPG suggested that the group III mGluRs were responsible for ACPD-induced death. However, MCPG has previously been shown to be ineffective at antagonising responses mediated by the group III subtypes mGluR4 and mGluR7 (Hayashi et a!., 1994;Saugstad et al, 1994;Thomsen et a!., 1994). In addition, ACPD has generally been assumed to be relatively ineffective as an agonist at group III mGluRs, and cloned group ifi mGluRs are distinguished by their insensitivity to ACPD, and their sensitivity to L-AP4 (see Pin and Duvoisin, 1995).…”

Cyclothiazide selectively inhibits mGluR1 receptors interacting with a common allosteric site for non-competitive antagonists

“…5A and D). More importantly, 4C3HPG, which is a competitive antagonist of mGluR1a (Kingston et al, 1995) but an agonist of group II receptors (Hayashi et al, 1994), stimulated [Ca 2+ ] i increases in cells expressing both mGluR3/1a and mGluR2/1a chimeric receptors ( Fig. 5A and D).…”