Our group has previously synthesized and characterized a large series of substituted α-methyl phenylglycines. MCPG (α-methyl-4-carboxyphenylglycine) proved to be a low potency antagonist, having activity at group I,II and III mGlu receptors. Substitution of the 4-carboxy moiety by 4-phosphono yielded MPPG, which exhibited greatly increased potency and introduced selectivity for groups II/III.Extension of this synthetic strategy has led to the recent synthesis of (RS)-α-cyclopropyl-4-phosphonophenylglycine ((RS)-CPPG). In its ability to reverse both L-AP4 (group III) and L-CCG-I (group II)-mediated inhibition of forskolin-stimulated cAMP accumulation in adult rat cortex, CPPG showed a 20 fold selectivity versus L-AP4 (IC 5 0 =2.2nM). CPPG was a weak competitive antagonist at group I receptors mediating phosphoinositide hydrolysis in neonatal rat cortex (K B =0.7mM) and, at 100μM, was devoid of activity in cultured cerebellar granule cells. This high potency, and selectivity of CPPG for group III, compared with group II, mGlu receptors is similarly observed in its ability to reverse L-AP4 and (1S,3S)-ACPD-induced depression of the monosynaptic component of the DR-VRP. Here, CPPG displayed a 30-fold higher potency at the L-AP4-sensitive mGlu receptor.In experiments designed to investigate presynaptic mGlu autoreceptors which regulate glutamate release from cortical synaptosomes, L-AP4 and L-CCG-I-induced inhibitions of 4-aminopyridine (200μM)-evoked release were potently antagonized by CPPG, with a degree of selectivity for the group III receptors. In conclusion, CPPG provides a potent and selective agent for elucidation of group II/III mGlu receptor responses.