The effects of (RS)‐α‐cyclopropyl‐4‐phosphonophenylglycine ((RS)‐CPPG), a potent and selective metabotropic glutamate receptor antagonist

Abstract

1 In this study we describe the potent antagonist activity of a novel metabotropic glutamate (mGlu) receptor antagonist (RS)-α-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG) which exhibits selectivity for mGlu receptors (group II and III) negatively coupled to adenylyl cyclase 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) inhibition of forskolin-stimulated cyclic AMP accumulation were potently reversed by (RS)-CPPG (IC₅₀ values: 2.2 ± 0.6 nM and 46.2 ± 18.2 nM, respectively). 3 In contrast, (RS)-CPPG acted as a weak antagonist against group I mGlu receptors. In neonatal rat cortical slices, (RS)-CPPG antagonized (K_B = 0.65 ± 0.07 mM) (1S, 3R)-1-aminocyclopentane-1, 3-dicarboxylic acid ((1S, 3R)-ACPD)-stimulated phosphoinositide hydrolysis. (RS)-CPPG (100 μm) failed to influence L-quisqualate-stimulated 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 for group III mGlu receptors), having negligible activity at group I mGlu receptors.