Phenylglycine analogues as antagonists of either cloned or native group I metabotropic glutamate receptors on neonatal rat spinal motoneurones

To date, genes encoding eight metabotropic glutamate (mGlu) receptors have been isolated. They have been classified into three groups according to their sequence homology, agonist selectivity and signal transduction mechanism. Activation of group I mGlu receptors (mGlu1,5) results in an increase in both phosphoinositide hydrolysis and calcium mobilisation while activation of mGlu receptors in group II (mGlu2,3) or III (mGlu4,6,7,8) leads to a reduction in cAMP levels. In order to probe the physiological roles of the various mGlu receptor subtypes selective agonists and antagonists for these receptors are required. Phenylglycine (PG) analogues were amongst the first selective ligands developed for mGlu receptors. Of these, (S)-alpha -methyl-4-carboxy-PG (MCPG) was the first reported antagonist with action at all three groups of mGlu receptors and (S)-3,5-dihydroxy-PG was the first selective group I mGlu receptor agonist. Both have been widely used for the characterisation of the physiological roles of mGlu receptors but newer compounds with greater potency and selectivity for mGlu1 and mGlu5 are still required. In this review, the development of phenylglycine and related analogues as selective group I mGlu receptor antagonists will be outlined. In addition, the actions of four novel phenylglycine analogues: (RS)-alpha -xanthenylmethyl-4-carboxy-PG (LY339764), (RS)-alpha -thioxanthenylmethyl-4-carboxy-PG (LY367366), (RS)-alpha -xanthenylmethyl-4-tetrazolyl-PG (LY367586), and (S)-alpha -methyl-4-carboxy-PG (LY367385) on native and cloned mGlu receptor subtypes will be described.