Abstract: Discovery of mGlu receptors has dramatically influenced our understanding of glutamatergic neurotransmission in the central nervous system. This receptor family provides a mechanism by which activation by glutamate can regulate a number of important neuronal and glial functions that are not typically modulated by ligand-gated ion channels. This includes modulation of neuronal excitability, synaptic transmission, and various metabolic functions. Because of the ubiquitous distribution of glutamatergic synapses, discovery of the mGlu receptors immediately raised the likelihood that mGlu receptors would participate in most, if not all, major functions of the CNS. In addition, the wide diversity and heterogeneous distribution of mGlu receptor subtypes could provide an opportunity for development of pharmacological agents that selectively target specific CNS systems to achieve a therapeutic effect. Over the past decade, an increasing number of agonists and antagonists selective for specific mGlu receptor subtypes have been developed. Use of these pharmacological tools along with genetic approaches has led to major advances in our understanding of the roles of mGlu receptors in regulating CNS systems and animal behavior. These studies suggest that drugs active at mGlu receptors may be useful in treatment of a wide variety of neurological and psychiatric disorders.
2000. L-Glutamate as a central neurotransmitter: Looking back.
Biochem. Soc. Trans.
, J.V. Nadler & C.W. Cotman.
1979. The effect of acidic amino acid antagonists on synaptic transmission in the hippocampal formation in vitro.
& C.W. Cotman.
1981. Micromolar L-2-amino-4-phosphonobutyric acid selectively inhibits perforant path synapses from lateral entorhinal cortex.
& C.W. Cotman.
1982. Response of Schaffer collateral-CA1 cell synapses of the hippocampus to analogues of acidic amino acids.
& J.C. Watkins.
1982. Actions of D and L forms of 2-amino-5-phosphonovalerate and 2-amino-4-phosphonobutyrate in the cat spinal cord.
, A.A. Francis, A.W. Jones,
1982. The effects of a series of ω-phosphonic ω-carboxylic amino acids of electrically evoked and excitant amino acid-induced responses in isolated spinal cord preparations.
Br. J. Pharmacol.
, J.P. Pin, M. Recasens,
1985. Glutamate stimulates inositol phosphate formation in striatal neurones.
, M.J. Iadarola, J.T. Wroblewski & E. Costa.
1986. The activation of inositol phospholipid metabollism as a signal-transducing system for excitatory amino acids in primary cultures of cerebellar granule cells.
, J.L. Meek, M.J. Iadarola,
1986. Coupling of inositol phospholipid metabolism with excitatory amino acid recognition sites in rat hippocampus.
, I. Ito & C. Hirono.
1987. A new type of glutamate receptor linked to inositol phospholipids metabolism.
, M.J. Peet, D.S. Magnuson & H. McLennan.
1988. Synthesis, resolution, and absolute configuration of the isomers of the neuronal excitant 1-amino-1,3-cyclopentanedicarboxylic acid.
J. Med. Chem.
, D.T. Monaghan & C.W. Cotman.
1988. Glutamate receptors and phosphoinositide metabolism: stimulation via quisqualate receptors is inhibited by N-methyl-D-aspartate receptor activation.
& P.J Conn.
1990. Selective activation of phosphoinositide hydrolysis by a rigid analogue of glutamate.
& P.J Conn.
1991. Excitatory effects of ACPD receptor activation in the hippocampus are mediated by direct effects on pyramidal cells and blockade of synaptic inhibition.
, B.H. Gahwiler, K.Q. Do & T. Knopfel.
1990. Potassium conductances in hippocampal neurons blocked by excitatory amino-acid transmitters.
& R.C. Malenka.
1991. Agonists at metabotropic glutamate receptors presynaptically inhibit EPSCs in neuronal rat hippocampus.
, Y. Tanabe, K. Tsuchida,
1991. Sequence and expression of a metabotropic glutamate receptor.
, J.L. Kuijper, T.L. Gilbert,
1991. Cloning, expression, and gene structure of a G protein-coupled glutamate receptor from rat brain.
& J.P. Pin.
1997. Pharmacology and functions of metabotropic glutamate receptors.
Annu. Rev. Pharmacol. Toxicol.
1999. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity.
Brain Res. Brain Res. Rev.
, D.E. Jane & J.A. Monn.
1999. Pharmacological agents acting at subtypes of metabotropic glutamate receptors.
, R. Kuhn & J.P. Pin.
2002. Allosteric modulators of group I.
Metabotropic glutamate receptors: novel subtype-selective ligands and therapeutic perspectives. Curr. Opin. Pharmacol.
2001. Unveiling the functions of presynaptic metabotropic glutamate receptors in the central nervous system.
J. Pharmacol. Exp. Ther.
, F. Gasparini, T.E. Salt & R. Kuhn.
2001. Novel allosteric antagonists shed light on mglu5 receptors and CNS disorders.
Trends Pharmacol. Sci.
, L. Tehrani, J. Roppe,
2003. 3-[2-Methyl-1,3-thiazol-4-ylethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity.
J. Med. Chem.
, V. Mutel, S. Jolidon,
2001. Positive allosteric modulators of metabotropic glutamate 1 receptor: characterization, mechanism of action, and binding site.
Proc. Natl. Acad. Sci. USA