The metabotropic glutamate (mGlu) receptors are family of eight single polypeptide chain receptors that function via coupling to G-proteins. In common with other G protein coupled receptors (GPCRs), the mGlu receptors possess a 7 transmembrane domain motif (7-TMR)and an extracellular N-terminus and intracellular C-terminus. However, the mGlu receptors are much larger than GPCRs of the adrenergic type and the ligand binding domain is located in the N-terminus, not in a pocket formed from the clustering of the 7-TMR region (for more information on the structure and function of these receptors, click here).

The mGlu receptors have been divided into three groups based on sequence similarities, signal transduction systems and pharmacology. Until recently, few compounds existed that could distinguish between individual receptor subtypes. The situation, however, is changing rapidly. This page will provide information on the agonists and antagonists that are most useful for mGlu receptor research, many of which have been synthesised here in Bristol by David Jane and are available through Tocris Cookson. Click on the links for details of compounds that act on NMDA and AMPA receptors. Compounds named in Red are not yet commercially available; click on the y symbol to follow PubMed links. For a comprehensive review of metabotropic glutamate receptor pharmacology, see Schoepp, Jane & Monn (1999) Neuropharmacology 38; 1431-1476 [Medline]).

mGlu Receptor Agonists

This section will describe the compounds that act as agonists at the different groups of mGlu receptors. For a more detailed discussion of how the EC50's or IC50's given were obtained, see the review quoted above.

Group I mGlu Receptor Agonists One of the most commonly used agonists for the Group I mGlu receptors is (S)-3,5-DHPG. This compound selectively activates mGlu1 and mGlu5 receptors with EC50 values below 10 µM, although it should be noted that in some cell lines expressing rat clones the affinity of (S)-3,5-DHPG for the group I mGlu receptors is closer to 30 µM. In addition, it also some activity at mGlu3 receptors, although none has been detected at any other currently known mGlu receptor sub-type. Another very useful compound is (RS)-CHPG. This was the first mGlu5 receptor selective agonist to be synthesised (in Bristol). Within the group I receptors, (RS)-CHPG is only active at the mGlu5 receptor sub-type and, despite it's low affinity, has been used to identify roles this receptor sub-type plays in synaptic plasticity. A further compound, Z-CBQA, has recently been synthesised that is also mGlu5 receptor selective, with a nearly 70-fold increase in affinity over (RS)-CHPG

Group II mGlu Receptor Agonists A number of agonists that are selective for group II mGlu receptors are available. The most potent of these is LY354740. This compound has an affinity in the nanomolar range for these receptors, with a slight selectivity for mGlu2 over mGlu3 receptors. Another useful compound is (2R,4R)-APDC, which shows a 275-fold greater affinity for group II receptors than any other mGlu receptor, making this agonist the best tool available for studying group II mGlu receptors. DCG-IV is a widely used group II mGlu receptor agonist, with an EC50 value for the inhibition of forskolin stimulated cAMP synthesis in the sub-micomolar range. However, the use of this compound is complicated by the fact that it is an antagonist at both group I and Group III receptors and an agonists at NMDA receptors. Previously described group II mGlu receptor agonists such as (1S,3S)-ACPD and L-CCG-I are less useful as they have significant agonists action at other mGlu receptor subtypes.

Group III mGlu Receptor Agonists The most widely used group III mGlu receptor agonist is L-AP4, a glutamate analogue that was used in the early 1980's to suggest the involvement of pre-synaptic glutamate receptors in controlling glutamate release. In addition, this compound, and the closely releated L-AP3, were shown to block the 'metabotropic' actions of ibotentate (a broad spectrum glutamate receptor agonist) and were instrumental in the development of the notion of metabotropic glutamate receptors long before they were cloned. Other widely used agonists are L-SOP and more recently (RS)-PPG. Within the group III receptors, (RS)-PPG shows an ~20-fold selectivity for mGlu8 over mGlu4 or mGlu6 receptors. More recently still, a highly potent mGlu8 receptor selective agonist has been reported from Dr David Jane's laboratory, (S)-3,4-DCPG. This compound activates mGlu8a receptors with nanomolar potency and shows >280 fold selectivity over any other centrally expressed mGlu receptor subtype. (S)-3,4-DCPG is therfore likely to become the agonist of choice for the study of mGlu8 receptor function. Other agonists show no particular selectivity for any of the group III receptors, although (S)-HomoAMPA appears to selectively activate mGlu6 receptors ( it possesses neither agonist or antagonist activity in cell lines expressing either group I or group II mGlu receptor subtypes but no information is available regarding the activity of this compound on mGlu8 receptors).

mGlu Receptor Antagonists

This section will describe the most useful antagonists for the mGlu receptors, indicating which compounds display subtype selectivity. Antagonist pharmacology of the mGlu receptors is complex, with some compounds acting as an antagonist at one receptor subtype but an agonist at another. In addition, some antagonists display agonist-dependent antagonism i.e the potency of an antagonist is dependent on the agonist used to elicit the functional response to be inhibited. This phenomenon is particularly noticable with group I mGlu receptor antagonists.

Broad spectrum mGlu Receptor Antagonists These compounds act at more than one group of mGlu receptors, and includes the most commonly used mGlu receptor antagonist, (S)-MCPG, a compound developed in Bristol. (S)-MCPG is a competitive antagonist of both group I and group II receptors, showing a degree of selectivity for mGlu1 over mGlu5 receptors within group I. There is some evidence that (S)-MCPG may display agonist-dependent antagonism at mGlu5 receptors, inhibiting (1S,3R)-ACPD-evoked but not L-glutamate-evoked phosphoinositide turnover. However, no difference has been detected in the ability of (S)-MCPG to block either L-glutamate- or (S)-DHPG-evoked calcium release. LY341495 and it's structurally related epimer, the recently reported LY344545 are two other compounds that, when used at high concentrations, are broad spectrum antagonists. However, at lower concentrations, these two compounds show different pharmalogical profiles. LY341495 is an extremely potent antagonist of group II mGlu receptors. Interestingly, some effects of (S)-MCPG are not reproduced by LY341495 suggesting that there may be more mGlu receptors that have yet to be cloned. Although for most mGlu receptors, LY344545 has a lower affinity, potency at mGlu5 receptors is slightly raised. Thus, importantly, LY344545 is a selective, competitive antagonist of mGlu5 receptors, within group I.

Group I mGlu Receptor Antagonists In addition to (S)-MCPG, it's parent compound, (S)-4-CPG is also a widely used group I mGlu receptor antagonist. Like (S)-MCPG, this compound is a competitive antagonist but has a greater degree of selectivity for mGlu1 receptors over mGlu5 receptors. Indeeed, in many studies it has been inactive at mGlu5 receptors, although the usefulness of (S)-4-CPG in neurons is limited by a weak agonist action at group II mGlu receptors. However, the 2-methyl derivative of (S)-4-CPG, 4C2MCPG (LY367385), has a higher potency and selectivity for mGlu1 receptors over mGlu5 receptors, with no effects on group II receptors. Hence, 4C2MCPG is the competitive antagonist of choice for the study of the physiological roles mGlu 1 receptors play in the CNS. The only competitive antagonist of mGlu5 receptors developed to date is the recently reported LY344545. This compound shows an eight-fold selectivity for mGlu5 receptors over mGlu1 receptors, although strong effects ate group II receptors ande weak NMDA receptor antagonist activity will probably resirict the usefullness of this compound. Other developments have led to the synthesis of selective non-competitive antagonists of the group I mGlu receptors. CPCCOEt, selectively antagonises mGlu1 receptors while MPEP is a highly potent mGlu5 receptor antagonist. These two compounds are likely to be widely used in the analysis of the functional roles of the group I mGlu receptors.

Group II mGlu Receptor Antagonists The group II mGlu receptor antagonist with the highest potency is currently LY341495, which acts at these receptors in the nanomaloar range. Indeed, LY341495 has recently been radiolabelled for radioligand binding studies. Although this compound acts at all other mGlu receptors (click here), its affinity for the group II receptors (~1 nM) will make it the antagonist of choice. Othe useful antagonists of group II mGlu receptors are ADED and EGlu, an ethyl- substituted L-glutamate analogue. Although less potent than LY341495, both EGlu and ADED are inactive at group I and group III receptors. Finally, (S)-MCPG is still widely used to study the physiological roles of the group II mGlu receptors.

Group III mGlu Receptor Antagonists Of the three groups of mGlu receptors, the group III receptors have been less studied. Hence fewer selective antagonists exist for these receptors. MAP4 and MSOP, the a-methyl derivatives of the group III receptor agonists, L-AP4 and L-SOP, are moderately potent competitive antagonists of these receptors, although MAP4 may actually have agonist activity at mGlu4 and mGlu6 receptors. In addition, one report has demonstrated significant agonist activity at mGlu2 receptors for both MSOP and MAP4. However, in the neonatal rat spinal cord assay, neither MAP4 or MSOP antagonised group II mGlu receptor-mediated depression of synaptic transmission. Two analogues of (S)-MCPG, MPPG and CPPG, have also been shown to be antagonists of the group III receptors with a higher potency and greater selectivity than MAP4 or MSOP. However, data on the ability of these compounds to antagonise individual receptor subtypes is scarce.