The metabotropic glutamate receptors (mGluRs) are family C G-protein-coupled receptors that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system. The mGluRs bind glutamate within a large extracellular domain and transmit signals through the receptor protein to intracellular signaling partners. A great deal of progress has been made in determining the mechanisms by which mGluRs are activated, proteins with which they interact, and orthosteric and allosteric ligands that can modulate receptor activity. The widespread expression of mGluRs makes these receptors particularly attractive drug targets, and recent studies continue to validate the therapeutic utility of mGluR ligands in neurological and psychiatric disorders such as Alzheimer's disease, Parkinson's disease, anxiety, depression, and schizophrenia.

Despite G-protein-coupled receptors (GPCRs) being among the most fruitful targets for marketed drugs, intense discovery efforts for several GPCR subtypes have failed to deliver selective drug candidates. Historically, drug discovery programmes for GPCR ligands have been dominated by efforts to develop agonists and antagonists that act at orthosteric sites for endogenous ligands. However, in recent years, there have been tremendous advances in the discovery of novel ligands for GPCRs that act at allosteric sites to regulate receptor function. These compounds provide high selectivity, novel modes of efficacy and may lead to novel therapeutic agents for the treatment of multiple psychiatric and neurological human disorders.G-protein-coupled receptors (GPCRs) are the largest class of cell-surface receptors and play crucial roles in virtually every organ system (see ref. 1 for review). GPCRs are activated by a diverse range of ligands, including hormones, neurotransmitters, ions, odorants and photons of light, and couple to a wide range of signalling molecules and effector systems. GPCRs have been implicated in a multitude of human disorders and numerous diseases have been linked to mutations and polymorphisms in GPCRs2,3. Thus, it is not surprising that GPCRs are the target of many therapeutic agents that are currently in use. It is estimated that nearly half of all modern drugs regulate GPCR activity in some way.However, despite the proven success of GPCRs as drug targets, useful ligands do not exist for the majority of GPCRs. GPCRs are encoded by more than 1,000 genes 4 , yet synthetic ligands for only a small fraction of these are available, and for many receptors intense efforts have failed to yield highly selective ligands that could ultimately be used as drug leads. A number of important issues contribute to the difficulty of discovering smallmolecule selective agonists or antagonists that act on the orthosteric site of some GPCRs. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptFor instance, the orthosteric binding sites across members of a single GPCR subfamily for a particular endogenous ligand are often highly conserved, making it difficult to achieve high selectivity for specific GPCR subtypes. Furthermore, ligands at orthosteric sites for some GPCRs, such as peptide or protein receptors, have other physicochemical and pharmacokinetic properties that are incompatible with scaffolds that are useful for smallmolecule drug discovery. An alternative approach, which has proven highly successful for ligand-gated ion channels, is the development of selective allosteric modulators of the specific receptor subtypes. These small molecules do not bind to the orthosteric ligand binding site but instead act at an alternatively located binding site (allosteric site), which is distinct from the orthosteric site, to either potentiate or inhibit activation of the receptor by its natural ligand. Benzodiazepines are a classic example of positive allosteric modulators of γ-aminobutyric acid...

In recent years, the metabotropic glutamate (mGlu) receptors have emerged as potential new drug targets for treatment of a range of CNS disorders. Some of the most compelling advances have been made in targeting specific mGlu receptor subtypes as a fundamentally new approach to the treatment of schizophrenia. Recent animal and clinical studies provide strong evidence that agonists of group II mGlu receptors (mGluR2 and mGluR3) are effective in the treatment of the positive symptoms of schizophrenia, and animal studies suggest that mGluR5 agonists could provide a novel approach for the treatment of all major symptom domains (positive, negative, and cognitive) of this disorder. Although the discovery of selective agonists of these receptors is a challenge, there have been recent advances in the discovery of highly selective positive allosteric modulators (PAMs) of mGluR2 and mGluR5. These mGlu receptor-selective PAMs have properties needed for optimization as clinical candidates and have robust effects in animal models that predict efficacy in treatment of schizophrenia.

The activation of group I metabotropic glutamate receptors (mGluRs) produces a variety of actions that lead to alterations in excitability and synaptic transmission in the CA1 region of the hippocampus. The group I mGluRs, mGluR1 and mGluR5, are activated selectively by (S)-3,5-dihydroxyphenylglycine (DHPG). To identify which of these mGluR subtypes are responsible for the various actions of DHPG in area CA1, we took advantage of two novel subtype-selective antagonists. (S)-(ϩ)-␣-amino-a-methylbenzeneacetic acid (LY367385) is a potent competitive antagonist that is selective for mGluR1, whereas 2-methyl-6-(phenylethynyl)-pyridine (MPEP) is a potent noncompetitive antagonist that is selective for mGluR5. The use of these compounds in experiments with whole-cell patch-clamp recording and Ca 2ϩ -imaging techniques revealed that each group I mGluR subtype plays distinct roles in regulating the function of CA1 pyramidal neurons. The block of mGluR1 by LY367385 suppressed the DHPG-induced increase in intracellular Ca 2ϩ concentration ([Ca 2ϩ ] i ) and the direct depolarization of CA1 hippocampal neurons. In addition, the increase in the frequency of spontaneous IPSCs (sIPSCs) caused by the DHPG-induced depolarization of inhibitory interneurons also was blocked by LY367385, as was the DHPG-induced inhibition of transmission at the Schaffer collateral3CA1 synapse. On the other hand, the block of mGluR5 by MPEP antagonized the DHPG-induced suppression of the Ca 2ϩ -activated potassium current (I AHP ) and potentiation of the NMDA receptor. Finally, antagonism of the DHPG-induced suppression of evoked IPSCs required the blockade of both mGluR1 and mGluR5. These data suggest that mGluR1 and mGluR5 play distinct roles in the regulation of the excitability of hippocampal CA1 pyramidal neurons. Key words: mGluR; mGluR1; mGluR5; (S)-3,5-dihydroxyphenylglycine (DHPG); (S)-(ϩ)-␣-amino-a-methylbenzeneacetic acid (LY367385); 2-methyl-6-(phenylethynyl)-pyridine (MPEP); I AHP ; IPSC; EPSC; hippocampusMetabotropic glutamate receptors (mGluRs) have been implicated in a number of physiological and pathological responses to glutamate in CA1 hippocampal region. These include the modulation of neuronal excitability and synaptic transmission (for review, see Anwyl, 1999) as well as the induction of long-term potentiation (Bashir et al., 1993), generation of epileptiform activity (Aronica et al

Novel allosteric modulators of G protein-coupled receptors (GPCRs) are providing fundamental advances in the development of GPCR ligands with high subtype selectivity and novel modes of efficacy that have not been possible with traditional approaches. As new allosteric modulators are advancing as drug candidates, we are developing an increased understanding of the major advantages and broad range of activities that can be achieved with these agents through selective modulation of specific signalling pathways, differential effects on GPCR homodimers versus heterodimers, and other properties. This understanding creates exciting opportunities, as well as unique challenges, in the optimization of novel therapeutic agents for disorders of the central nervous system.