THE EFFECTS OF (RS)-ALPHA-CYCLOPROPYL-4-PHOSPHONOPHENYLGLYCINE ((RS)-CPPG), A POTENT AND SELECTIVE METABOTROPIC GLUTAMATE-RECEPTOR ANTAGONIST

1 In this study we describe the potent antagonist activity of a novel metabotropic glutamate (mGlu) receptor antagonist (RS)-alpha-cycloprop yl-4-phosphonophenylglycine (RS)-CPPG) which exhibits selectivity for mGlu receptors (group II and III) negatively coupled to adenylyl cycla se in the adult rat cortex. 2 Both the L-2-amino-4-phosphonobutyrate ( L-AP4) and (2S, 1'S, 2'S)-2-(carboxycyclopropyl)glycine (L-CCG-1) inhi bition of forskolin-stimulated cyclic AMP accumulation were potently r eversed by (RS)-CPPG (I-50 values: 2.2 +/- 0.6 nM and 46.2 +/- 18.2 nM , respectively). 3 In contrast, (RS)-CPPG acted as a weak antagonist a gainst group I mGlu receptors. In neonatal rat cortical slices, (RS)-C PPG antagonized (K-B = 0.65 +/- 0.07 mM) (1S,3R)-1-aminocyclopentane-1 ,3-dicarboxylic acid ((1S,3R)-ACPD)-stimulated phosphoinositide hydrol ysis. (RS)-CPPG (100 mu M) failed to influence L-quisqualate-stimulate d phosphoinositide hydrolysis in cultured cerebellar granule cells. 4 In the rat cerebral cortex, (RS)-CPPG is the most potent antagonist of group II/III mGlu receptors yet described (with 20 fold selectivity f or group III mGlu receptors), having negligible activity at group I mG lu receptors.