The effects of (RS)‐α‐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)‐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 (KB = 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.