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

Abstract

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 mGluR1, mGluR2 and mGluR6 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,/mGluR6 or an antagonist activity on mGluR,.3 Carboxyphenylglycine derivatives showed an agonist activity on mGluR2 but an antagonist activity on mGluR1. 4 a-Methylation or a-ethylation of the carboxyphenylglycine derivatives converts the agonist property for mGluR2 to an antagonist property, thus producing antagonists at both mGluRj and mGluR2.5 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 ax-methyl derivatives of mGluR agonists. (2S, 1'S, 2'S)-2-(2-Carboxycyclopropyl)glycine (L-CCG-I) is a potent agonist for mGluR2 but a-methylation of this compound changes its activity to that of an mGluR2-selective antagonist. In contrast, a-methylation of L-2-amino-4-phosphonobutyrate (L-AP4) results in retention of an agonist activity on mGluR6. Thus, a-methylation produces different effects, depending on the chemical structures of lead compounds and/or on the subtype of mGluR tested.

When Are Class I Metabotropic Glutamate Receptors Necessary for Long-Term Potentiation?

“…The stronger the tetanization, the less potent were the mGluR antagonists MCPG and 4-CPG in affecting the time course of the resulting potentiation. MCPG has been characterized as a competitive antagonist of class I and class II mGluRs, whereas 4-CPG displays a selectivity toward class I mGluRs and only weak activity on mGluRs of class II (Davies et al, 1995;Sekiyama et al, 1996). Because in most of our experiments the results obtained with the two antagonists were very similar, the effects of these compounds on LTP may be assigned to an action on class I mGluRs.…”

“…somewhat lower affinity at mGluRs of class II (Davies et al, 1995;Sekiyama et al, 1996), we repeated the same experiments with 4-CPG, which represents in the employed concentration range a specific antagonist toward class I mGluRs. 4-C PG (100 M) had no effect on the initial potentiation (4-C PG group: 208 Ϯ 9%, n ϭ 7; control: 206 Ϯ 10%, n ϭ 7) and the maintenance of LTP (240 min after tetanus: 135 Ϯ 8% and 132 Ϯ 6%, respectively) ( Fig.…”

Blunted cystine–glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking

“…Moreover, we found that this effect is blocked by infusion of the cystine-glutamate exchange inhibitor CPG into the nucleus accumbens. Because CPG also acts at metabotropic glutamate receptors, we selected a concentration (500 nM) that is significantly lower than the EC50s of CPG to block group I mGluRs (40-65 µM) or stimulate group II mGluRs (570-970 µM) (Cavanni et al, 1994;Thomsen et al, 1994;Sekiyama et al, 1996). As a result, the present findings indicate that N-acetylcysteine blocks cocaine-induced reinstatement of drug seeking by targeting cystine-glutamate exchange by system x c -in the nucleus accumbens.…”

Partial Involvement of Group I Metabotropic Glutamate Receptors in the Neurotoxicity of 3-N-Oxalyl-L-2,3-diaminopropanoic Acid (L-.BETA.-ODAP)

“…Within these limitations, the receptors seemed to have no effect on the neurotoxicity of L-b -ODAP in rat primary cortical neurons. Although MCPG acts on both group I and group II mGluRs as an antagonist, 29) the fact that MCPG was almost as effective as AIDA also excludes the possibility that group II mGluRs are involved in the neurotoxicity of L-b -ODAP.…”