Phenylglycine derivatives as new pharmacological tools for investigating the role of metabotropic glutamate receptors in the central nervous system

Abstract

The possible roles of G-protein coupled metabotropic glutamate receptors in central nervous function are currently the focus of intensive investigation. 2,10,20,33 The complexity of effects produced by agonists at these receptors probably reflects the activity of a range of sub-types. The metabotropic glutamate receptors first described 23,24,28,35,38 are linked to phospholipase C, mediating phosphoinositide hydrolysis and release of Ca 2+ from intracellular stores. 12,14,15,21,22 A substance generally considered to be a selective agonist for these receptors is (1S,3R)-1-aminocyclopentane-1,3-dicar-boxylic acid (ACPD). 17,27 This substance not only stimulates phosphoinositide hydrolysis, but also inhibits cyclic AMP formation. 7,34 A family of metabotropic glutamate receptors, incorporating both phospholipase C- and adenylcyclase-Iinked sub-types has been cloned. 40 Various effects of metabotropic glutamate receptor agonists on membrane ion fluxes and synaptic events have been reported, including neuronal depolarization and/or excitation, 8,9,11,18,32,36,37 hyperpolarization, 16 inhibition of Ca 2+-dependent and voltage-gated K + currents, 3,9,36,37 potentiation of N-methyl- d-aspartate-induced responses, 1,16 depression of synaptic excitation 4,29 and either induction 6 or augmentation 19,26 of long-term potentiation. To clarify the role of metabotropic glutamate receptors in central nervous activity and to aid the characterization of the various receptor types that may be involved, a range of highly selective agonists and antagonists is required. To date, currently available antagonists such as l-2-amino-3-phosphonopropionate 33 and l-aspartic acid-β-hydroxamate 25,30 appear to be unselective and insufficiently potent. 8,30,32,33 We report here the actions of three phenylglycine derivatives, the particular agonist and/or antagonist properties of which may help to elucidate the roles of metabotropic glutamate receptors in central nervous activity. (S)-4-Carboxyphenylglycine is a competitive antagonist of ACPD-stimulated phosphoinositide hydrolysis in neonatal rat cerebral cortex slices. In the same system, (S)-3-hydroxyphenylglycine and (S)-4-carboxy-3-hydroxyphenylglycine are moderate and weak agonists, respectively, both of lower efficacy than ACPD, but without ability to lower the maximal stimulation produced by ACPD. l-2-Amino-3-phos-phonopropionate is an uncompetitive antagonist of both ACPD- and (S)-3-hydroxyphenylglycine-stimulated phosphoinositide hydrolysis. All three phenylglycine derivatives, but not l-2-amino-3-phosphonopropionate, antagonize ACPD-induced depolarization in neonatal rat motoneurons and excitation in rat thalamic neurons. The results suggest differences at either the receptor or effector system level between ACPD-stimulated metabotropic glutamate receptors in cortex and the receptors mediating depolarizing/excitatory effects in motoneurons and thalamic neurons.