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mGlu Receptors-Briston

时间:2005-11-15 19:00来源:www.bris.ac.uk 作者:bioguider 阅读:

mGlu Receptors

(updated March 18, 2002)

 

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

 
 
(S)-3,5-DHPG
(RS)-CHPG
Z-CBQA
   
EC 50 Values (µM)
Group I
mGlu 1
6
>10000
>100
mGlu 5
2
750
11
   
Group II
mGlu 2
>1000
-
>100
mGlu 3
106
-
-
   
Group III
mGlu 4
>1000
-
>100
mGlu 6
-
-
-
mGlu 7
>1000
-
-
mGlu 8
>1000
-
-
 
 

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.

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