Structure‐activity relationships of new agonists and antagonists of different metabotropic glutamate receptor subtypes

1 We investigated the agonist and antagonist activities of 22 new phenylglycine and phenylalanine derivatives for metabotropic glutamate receptors (mGluRs) by examining their effects on the signal transduction of mGluR 1 , mGluR 2 and mGluR 6 subtypes expressed in Chinese hamster ovary cells. This analysis revealed several structural characteristics that govern receptor subtype specificity of the agonist and antagonist activities of phenylglycine derivatives. 2 Hydroxyphenylglycine derivatives possessed either an agonist activity on mGluR 1 /mGluR 6 or an antagonist activity on mGluR 1 . 3 Carboxyphenylglycine derivatives showed an agonist activity on mGluR 2 but an antagonist activity on mGluR 1 . 4 α‐Methylation or α‐ethylation of the carboxyphenylglycine derivatives converts the agonist property for mGluR 2 to an antagonist property, thus producing antagonists at both mGluR 1 and mGluR 2 . 5 Structurally‐corresponding phenylalanine derivatives showed little or no agonist or antagonist activity on any subtypes of the receptors. 6 This investigation demonstrates that the nature and positions of side chains and ring substituents incorporated into the phenylglycine structure are critical in determining the agonist and antagonist activities of members of this group of compounds on different subtypes of the mGluR family. 7 We also tested two α‐methyl derivatives of mGluR agonists. (2S, 1′S, 2′S)‐2‐(2‐Carboxycyclopropyl)glycine (L‐CCG‐I) is a potent agonist for mGluR 2 but α‐methylation of this compound changes its activity to that of an mGluR 2 ‐selective antagonist. In contrast, α‐methylation of L‐2‐amino‐4‐phosphonobutyrate (L‐AP4) results in retention of an agonist activity on mGluR 6 . Thus, α‐methylation produces different effects, depending on the chemical structures of lead compounds and/or on the subtype of mGluR tested.