Structure-activity relationships for a series of phenylglycine derivatives acting at metabotropic glutamate receptors (mGluRs)

摘要

1 The actions of a series of twelve phenylglycine derivatives at metabotropic glutamate receptors (mGluRs) linked to both phosphoinositide hydrolysis (PI) and cyclic AMP were investigated. 2 PI hydrolysis was determined by the accumulation of [~3H]-inositol-monophosphate ([~3H]-IP_1) in neonatal rat cortical slices prelabelled with [~3H]-myo-inositol. The non-selective mGluR agonist (1S,3R)-1 - aminocyclopentane - 1,3 - dicarboxylic acid ((1S,3R)-ACPD) produced a concentration-dependent increase in [~3H]-IP_1 (EC_(50) ≈ 20 μM). This agonist was subsequently used to investigate potential antagonist activity of the phenylglycine derivatives. Of the compounds tested (+ )-α-methyl-4-carboxyphenylglycine (M4CPG) and (RS)-α-ethyl-4-carboxyphenylglycine (E4CPG) were the most active with K_B values of 0.184 ± 0.04 mM and 0.367 ± 0.2 mM respectively. 3 Activity at adenylyl cylase-coupled mGluRs was investigated by determining the accumulation of [~3H]-cyclic AMP in adult rat cortical slices. [~3H]-cyclic AMP accumulation, elicited by 30 μM forskolin, was inhibited by (2S,3S,4S)-α-(carboxycyclopropyl)glycine (L-CCG-1) and L-2-amino-4-phosphonobu-tanoate (L-AP4) with respective EC_(50) values of 0.3 μM and 10 μM. Neither agonist was able to inhibit completely forskolin stimulated cyclic AMP accumulation; this is evidence that not all adenylyl cyclase is susceptible to modulation by mGluRs. Phenylglycine derivatives were examined for their ability to antagonize the inhibition of [~3H]-cyclic AMP accumulation by L-CCG-1 or L-AP4 at their EC_(50) concentrations. 4 A rank order of potency of the phenylglycine derivatives as antagonists of L-AP4 and L-CCG-1 was obtained. The most effective compound, (RS)-α-methyl-3-carboxymethylphenylglycine (M3CMPG) had IC_(50) values in the order of 1 μM against L-AP4 and 0.4 μM against L-CCG-1. 5 The results from this study indicate that phenylglycine-derived compounds can discriminate between groups of metabotropic glutamate receptors and may also display some selective activity between subtypes within groups. Future work based on these findings may lead to the development of more selective and potent compounds as important pharmacological tools.