STRUCTURE-ACTIVITY-RELATIONSHIPS FOR A SERIES OF PHENYLGLYCINE DERIVATIVES ACTING AT METABOTROPIC GLUTAMATE RECEPTORS (MGLURS)

1 The actions of a series of twelve phenylglycine derivatives at metab otropic glutamate receptors (mGluRs) linked to both phosphoinositide h ydrolysis (PI) and cyclic AMP were investigated. 2 PI hydrolysis was d etermined by the accumulation of [H-3]-inositol-monophosphate ([H-3]-I P1) in neonatal rat cortical slices prelabelled with [H-3]-myo-inosito l. The non-selective mGluR agonist (1S,3R)-1-aminocyclopentane-1,3-dic arboxylic acid ((1S,3R)-ACPD) produced a concentration-dependent incre ase in [H-3]-IP1 (EC(50) approximate to 20 mu M) This agonist was subs equently used to investigate potential antagonist activity of the phen ylglycine derivatives. Of the compounds tested (+)-alpha-methyl-4-carb oxyphenylglycine (M4CPG) and (RS)-alpha-ethyl-4-carboxyphenylglycine ( E4CPG) were the most active with K-B values of 0.184+/-0.04 mM and 0.3 67+/-0.2 mM respectively. 3 Activity at adenylyl cylase-coupled mGluRs was investigated by determining the accumulation of [H-3]-cyclic AMP in adult rat cortical slices. [H-3]-cyclic AMP accumulation, elicited by 30 mu M forskolin, was inhibited by (2S,3S,4S)-alpha-(carboxycyclop ropyl)glycine (L-CCG-1) and L-2-amino-4-phosphonobutanoate (L-AP4) wit h respective EC(50) values of 0.3 mu M and 10 mu M. Neither agonist wa s able to inhibit completely forskolin stimulated cyclic AMP accumulat ion; this is evidence that not all adenylyl cyclase is susceptible to modulation by mGluRs. Phenylglycine derivatives were examined for thei r ability to antagonize the inhibition of [H-3]-cyclic AMP accumulatio n by L-CCG-1 or L-AP4 at their EC(50) concentrations. 4 A rank order o f potency of the phenylglycine derivatives as antagonists of L-AP4 and L-CCG-1 was obtained. The most effective compound, (RS)-alpha-methyl- 3-carboxymethylphenylglycine (M3CMPG) had IC50 values in the order of 1 mu M against L-AP4 and 0.4 mu M against L-CCG-1. 5 The results from this study indicate that phenylglycine-derived compounds can discrimin ate between groups of metabotropic glutamate receptors and may also di splay some selective activity between subtypes within groups. Future w ork based on these findings may lead to the development of more select ive and potent compounds as important pharmacological tools.