STRUCTURE-ACTIVITY-RELATIONSHIPS OF NEW AGONISTS AND ANTAGONISTS OF DIFFERENT METABOTROPIC GLUTAMATE-RECEPTOR SUBTYPES

1 We investigated the agonist and atagonist activities of 22 new pheny lglycine and phenylalamine derivatives for metabotropic glutamate rece ptors (mGluRs) by examining their effects on the signal transduction o f mGluR(1), mGluR(2) and mGluR(6) subtypes expressed in Chinese hamste r ovary cells. This analysis revealed several structural characteristi cs that govern receptor subtype specificity of the agonist and antagon ist activities of phenylglycine derivatives. 2 Hydroxyphenylglycine de rivatives possessed either an agonist activity on mGluR(1) mGluR(6) or an antagonist activity on mGluR(1). 3 Carboxyphenylglycine derivative s showed an agonist activity on mGluR(2) but an antagonist activity on mGluR(1). 4 alpha-Methylation or alpha-ethylation of the carboxypheny lglycine derivatives converts the agonist property For mGluR(2) to an antagonist property, thus producing antagonists at both mGluR(1) and m GluR(2). 5 Structurally-corresponding phenylalanine derivatives showed little or no agonist or antagonist activity on any subtypes of the re ceptors. 6 This investigation demonstrates that the nature and positio ns of side chains and ring substituents incorporated into the phenylgl ycine structure are critical in determining the agonist and antagonist activities of members of this group of compounds on different subtype s of the mGluR family. 7 We also tested two alpha-methyl derivatives o f mGluR agonists. (2S, 1'S, 2'S)-2-(2-Carboxycyciopropyl)glycine (L-CC G-I) is a potent agonist for mGluR(2) but alpha-methylation of this co mpound changes its activity to that of an mGluR(2)-selective antagonis t. In contrast, alpha-methylation of L-2-amino-4-phosphonobutyrate (L- AP4) results in retention of an agonist activity on mCluR(6). Thus, al pha-methylation produces different effects, depending on the chemical structures of lead compounds and/or on the subtype of mGluR tested.