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Glutamate Receptors (G Protein Family)

The existence of G protein-coupled glutamate receptors (also called "€œmetabotropic" glutamate or mGlu's), belonging to the seven transmembrane spanning superfamily of receptors, was shown definitively with the cloning of the first member in 1991. Since then, eight receptors of this class have been discovered. mGlu's are members of the "€œClass C"€ subgroup of G protein-coupled receptors, distinguished by the presence of a large N-terminal domain, which contains the orthosteric agonist binding site. Based on studies with mGlu1, these receptors are proposed to exist as homodimers with the N-terminal domain forming a "clam shell" structure consisting of two lobes linked by a hinge region. Glutamate binds between these lobes to stabilize a closed state that transduces a conformational change in the transmembrane regions of the homodimer to promote G-protein coupling. The existence of C-terminal splice variants for many subtypes and intracellular interacting proteins (e.g. Homer, Pick-1) suggests that mGlu receptor function is subject to complex intracellular regulation.

The eight receptors have been classified into three groups based on similarities in their amino acid sequences, G-protein coupling and pharmacology. Group I (mGlu1 and 5) couple to Gq and signal through inositol phospholipid breakdown whereas Group II (mGlu2 and 3) and Group III (mGlu4, 6, 7 and 8) couple to Gi/o and inhibit adenylyl cyclase. In addition, members of all three groups can interact directly with voltage-gated calcium or potassium channels though their G proteins. Numerous pharmacological tools for these receptors exist. These include several "Group-selective"€ agonists, specifically: quisqualate and S-DHPG for Group I; 2R,4R-APDC and LY-354740 for Group II; as well as L-AP-4 and RS-PPG for Group III. Likewise, several "€œGroup-selective"€ antagonists have been identified, specifically: LY393675 for Group I; LY341495 and MGS0039 for Group II; as well as MAP4 and UPB1110 for Group III.

Subtype-selective ligands for some of the mGlu receptors have also been described. In Group I, selective antagonists for mGlu1 include the competitive antagonist LY-367385; and the non-competitive antagonists CPCCOEt, R214127 and BAY63-7620. CHPG is a selective, but relatively low potency, agonist for mGlu5 receptors and selective non-competitive antagonists include MPEP, MTEP and DeMeOB. In Group II, the naturally occurring dipeptide NAAG is a selective agonist for mGlu3 receptors. Subtype selective agents within Group III have been less forthcoming, although (S)-homoAMPA is a weak, but selective agonist for mGlu6 receptors, and (S)-3,4-DCPG is a potent and selective agonist for mGlu8 receptors.

An exciting development in mGlu pharmacology is the discovery of allosteric modulators of several subtypes. These compounds bind in the 7-transmembrane domains to either positively or negatively modulate receptor activation by glutamate. The subtype selective "€œnon-competitive antagonists" described above act in this way. In addition, positive allosteric modulators (which do not directly activate the receptor, but produce a leftward shift in the agonist dose-response curve) have been identified, e.g.: Ro 67-7476 and Ro 01-6128 for mGlu1, CPPHA, DFB and CDPPB for mGlu5, LY-487379 for mGlu2 and PHCCC for mGlu4. Interestingly, a "€œneutral" modulator for mGlu5 has also been identified (DCB), that blocks the action of positive and negative allosteric modulators at this subtype without altering the glutamate-site binding or receptor activation. From a therapeutic perspective, allosteric modulators are an attractive approach since they typically exhibit high affinity, excellent subtype selectivity, have better "€œdrug-like"€ properties (e.g. blood/brain barrier penetration) than glutamate analogs acting at the transmitter recognition site, and act to either up or down regulate the actions of the glutamate at the targeted subtype in concert with neurotransmitter release.

In general, all three groups of G protein-coupled glutamate receptors are widely distributed throughout the CNS and evidence exits for postsynaptic, presynaptic and, in some cases, glial localization. One or more of the Group II and Group III receptors are believed to function as an autoreceptor, mediating of glutamate release from its nerve terminals. Presynaptic Group II and III receptors directly decrease the release of other neurotransmitters (for example dopamine and GABA) acting as hetereo-autoreceptors. In contrast, a presynaptic Group I receptor may promote glutamate release. Interestingly, a variant of mGlu4 with a truncated N-terminal domain exists on taste buds and is proposed to give rise to umami, the characteristic taste of monosodium glutamate. Activation of (presumably) postsynaptic Group I receptors potentiates NMDA receptor function. mGlu1 and mGlu5 agonists and positive allosteric modulators have been proposed as a novel approach to treat schizophrenia, whereas antagonists at these subtypes have been proposed as potential treatments for pain, drug addiction, anxiety, Parkinson'€™s disease and obesity, and also possess neuroprotective and anti-epileptic properties. Group II receptor agonists and positive allosteric modulators are effective in animal models of epilepsy, anxiety and psychosis, and LY354740 has been reported to be effective in patients with generalized anxiety. Group III agonists and positive allosteric modulators are effective in animal models of epilepsy, are neuroprotective and reverse the motor dysfunction in animal models of Parkinson's disease.


The Table below contains accepted modulators and additional information. For a list of additional products, see the "Similar Products" section below.


Currently Accepted Name mGlu1 mGlu5 mGlu2 mGlu3
Group Classification Group I Group I Group II Group II
Structural Information 1194 aa (human) 1212 aa (human) 872 aa (human) 879 aa (human)
Glutamate-site Agonists S-DHPG (D3689)
Quisqualate (Q2128)
S-DHPG (D3689)
Quisqualate (Q2128)
CHPG (C7743)
2R,4R-APDC (A7361)
LY-354740 (L1045)
MGS 0039
NAAG (A5930)
2R,4R-APDC (A7361)
LY-354740 (L1045)
Glutamate-site Antagonists LY-367385 (L4420)
Not Known LY341495c
MGS 0039
MGS 0039
Positive Allosteric Modulatorsb Ro 67-7476
Ro 01-6128
CPPHA (C2247)
DFB (D0943)
LY-487379 (L1170)
Not Known
Allosteric Antagonist b CPCCOEt
MPEP (M5435)
SIB-1757 (S9186)
SIB-1893 (S9311)
MTEP (M4699)
DMeOB (D6317)
DCB (D1068) (neutral ligand)
Not Known Not Known
Signal Transduction Mechanisms Gq/11 (increase IP3/DAG) Gq/11 (increase IP3/DAG) Gi (cAMP modulation) Gi (cAMP modulation)
Radioligands of Choice [3H]-Quisqualate
[3H]-Quisqualate [3H]-LY354740
Tissue Expression The expression of mGluRs is widespread in the CNS, with the exception of mGluR6 which is found almost exclusively in retina
Physiological Function Group I: mGluRs facilitate glutamate neurotransmission Group II: mGluRs generally inhibit glutamate and GABA-mediated neurotransmission
Disease Relevance Group I: schizophrenia, pain, drug addiction, anxiety, Parkinson'€™s disease, obesity, stroke and TBI, epilepsy Group II: anxiety, epilepsy, psychosis



Currently Accepted Name mGlu4 mGlu6 mGLu7 mGlu8
Group Classification Group III Group III Group III Group III
Structural Information 912 aa (human) 853 aa (human) 915 aa (human) 908 aa (human)
Glutamate-site Agonists L-AP-4 (A7929)
L-SOP (P0878)
RS-PPG (G6298)
L-AP-4 (A7929)
L-SOP (P0878)
RS-PPG (G6298)
L-AP-4 (A7929) L-AP-4 (A7929)
L-SOP (P0878)
RS-PPG (G6298)
MAP4 (M5560)
MAP4 (M5560)
MAP4 (M5560)
MAP4 (M5560)
Positive Allosteric
PHCCC Not Known
Not Known
Not Known
Allosteric Antagonist b Not Known
Not Known
Not Known
Not Known
Signal Transduction
Gi (cAMP modulation) Gi (cAMP modulation) Gi (cAMP modulation) Gi (cAMP modulation)
Radioligands of Choice [3H]-L-AP4 [3H]-L-AP4
Tissue Expression The expression of mGluRs is widespread in the CNS, with the exception of mGluR6 which is found almost exclusively in retina
Physiological Function Group III: mGluRs generally inhibit glutamate and GABA-mediated neurotransmission
Disease Relevance Group III: Parkinson'€™s disease, stroke, TBI, epilepsy



a) G Protein family is also referred to as metabotropic.

b) Allosteric ligands bind outside of the glutamate recognition site and either positively modulate glutamate response, act as non-competitive antagonists or neutral ligands blocking allosteric site interaction only.

c) Also significant antagonism of Group I and Group III receptors.

d) In cell lines expressing recombinant receptor subtypes.



L-AP-4: 2-Amino-4-phosphonobutyric acid
(2R,4R)-APDC: (2R,4R)-Aminopyrrolidine-2,4-dicarboxylic acid
BAY36-7620: (3aS,6aS)-6a-Naphtalen-2-ylmethyl-5-methyliden-hexahydro-cyclopental[c]furan-1-on
z-CBQA: (Z)-1-Amino-3-[2′€™-(3′€™,5′€™-dioxo-1′€™,2′€™,4′€™-oxadiazolidinyl-cyclobutane-1-carboxylic acid
CDPPB: 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide
CHPG: (R/S)-2-Chloro-5-hydroxyphenylglycine
Compound 4: 1-(2-Hydroxy-3-propyl-4-[4-[4-(2H-tetrazol-5-yl)phenoxy]-butoxy]phenyl)ethanone –€“ see Pinkerton, et al., J. Med. Chem., 47, 4595 (2004).
Compound 10: 2-[2-[3-(Pyridine-3-yloxy)phenyl]-2H-tetrazole-5-yl]pyridine –€“ see Huang, et al., Bioorg. Med. Chem. Lett., 14, 5473 (2004)
CPCCOEt: 7-Cyclopropan[b]chromen-1a-carboxylic acid ethyl ester
CPPHA: N-[4-Chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl]-2-hydroxybenzamide
DCG-IV: (2S,1'R,2'R,3'R)-2-(2,3 Dicarboxycyclopropyl)glycine
DCB: 3,3′€™-Dichlorobenzaldazine
DFB: 3,3′-Difluorobenzaldazine
DMeOB: 3,3′€™-Dimethoxybenzaldazine
S-DHPG: (R,S)-3,5-Dihydroxyphenylglycine
S-3,4-DCPG: (S)-3,4-Dicarboxyphenylglycine
E-GLU: (S)-α-Ethylglutamic acid
S-Homo-AMPA: (RS)-2-Amino-4-(3-hydroxy-5-methylisoxazol-4-yl)butyric acid
LY341495: (2S)-2-Amino-2-(1S,2S-2-carboxycyclopronan-1-yl-3-(xanth-9-yl)propanoic acid
LY354740: (+)-2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
LY367385: (+)-2-Methyl-4-carboxyphenylglycine
LY379268: (–€“)-2-Thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylate
LY487379: 2,2,2-Trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulfonamide
MAP4: (S)-2-Amino-2-methyl-4-phosphonobutyric acid
MGS 0039: (1R,2R,3R,5R,6R)-2-Amino-3-(3,4-dichlorobenzyloxy)-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid
MPEP: 2-Methyl-6-(phenylethynyl)pyridine
MTEP: 3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]pyridine
NAAG: N-Acetyl-L-aspartyl-l-glutamic acid
PHCCC: N-Phenyl-7-(hydroxylimino)cyclopropa[b]-chromen-1a-carboxamide
Ro 01-6128: Diphenylacetyl-carbamic acid ethyl ester
Ro 67-7476: (S)-2-(4-Fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidine
R214127: 1-(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone
RS-PPG: (RS)-4-Phosphonophenylglycine
SIB-1757: 6-Methyl-2-(phenylazo)-pyridinol
SIB-1893: (E)-2-Methyl-6-(2-phenylethenyl)pyridine
L-SOP: L-Serine-O-phosphate
UBP1110: (RS)-α-Methyl-3-chloro-4-phosphonophenylglycine


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