Metabotropic glutamate receptors
More information on this family may be found on the IUPHAR-DB family and introduction pages.
Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors, [56]) are activated by the endogenous ligands L-glutamic acid, L-aspartic acid, L-serine-O-phosphate (L-SOP), N-acetylaspartylglutamate (NAAG) and L-cysteine sulphinic acid. Examples of agonists selective for mGlu receptors compared with ionotropic glutamate receptors are (1S,3R)-ACPD and L-CCG-I, which show limited selectivity for Group II receptors. An example of an antagonist selective for mGlu receptors is LY341495, which blocks mGlu2 and mGlu3 at low nanomolar concentrations, mGlu8 at high nanomolar concentrations, and mGlu3, mGlu4, mGlu5 and mGlu7 in the micromolar range [24]. Three groups of native receptors are distinguishable on the bases of similarities of agonist pharmacology, primary sequence and G-protein effector coupling: Group I (mGlu1 and mGlu5), Group II (mGlu2 and mGlu3) and Group III (mGlu4, mGlu6, mGlu7 and mGlu8) (see Further reading). Group I mGlu receptors may be activated by 3,5-DHPG and (S)-3HPG [5] and antagonized by (S)-hexylhomoibotenic acid [35].
Group II mGlu receptors may be activated by LY389795 [43], LY379268 [43], LY354740 [57,67], DCG-IV and (2R,3R)-APDC [58], and antagonised by eGlu (4.3, [21] and LY307452 [15,66]. Group III mGlu receptors may be activated by (R,S)-4-PPG [18].
In addition to orthosteric ligands that directly interact with the glutamate recognition site directly, allosteric modulators have been described. Negative allosteric modulators are listed separately. The positive allosteric modulators most often act as ‘potentiators’ of an orthosteric agonist response, without significantly activating the receptor in the absence of agonist.
Unless otherwise stated all data refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).
Receptors 
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The activity of NAAG as an agonist at mGlu3 receptors was questioned on the basis of contamination with glutamate [9,16], but this has been refuted [47].
Radioligand binding using a variety of radioligands has been conducted on recombinant receptors (for example, [3H]R214127 [30] and [3H]YM298198 [28] at mGlu1 receptors and [3H]M-MPEP [17] and [3H]methoxymethyl-MTEP [1] at mGlu5 receptors. Although a number of radioligands have been used to examine binding using native tissues, correlation with individual subtypes is limited. Many pharmacological agents have not been fully tested across all known subtypes of mGlu receptors. Potential differences linked to the species (e.g. human versus rat or mouse) of the receptors and the receptor splice variants are generally not known. The influence of receptor expression level on pharmacology and selectivity has not been controlled for in most studies, particularly those involving functional assays of receptor coupling.
(S)-(+)-CBPG is an antagonist at mGlu1, but is an agonist (albeit of reduced efficacy) at mGlu5 receptors. DCG-IV also exhibits agonist activity at NMDA glutamate receptors [64]. A potential novel metabotrophic glutamate receptor coupled to phosphoinositide turnover has been observed in rat brain; it is activated by 4-methylhomoibotenic acid (ineffective as an agonist at recombinant Group I metabotrophic glutamate receptors), but resistant to LY341495 [10]. There are also reports of a distinct metabotrophic glutamate receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification [26,51]
All selective antagonists at metabotropic glutamate receptors are competitive.