Glutamate, metabotropic

Overview: Metabotropic glutamate (mGlu) receptors (nomenclature as agreed by NC-IUPHAR Subcommittee on Metabotropic Glutamate Receptors, Schoepp et al., 2000) are activated by the endogenous ligands L-glutamate, L-aspartate, L-serine-O-phosphate (LSOP), N-acetylaspartylglutamate (NAAG) and L-cysteine sulphonic 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 mGlu₁, mGlu₄, mGlu₅ and mGlu₇ in the micromolar range (Kingston et al., 1998). 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 DHPG and 3HPG (Brabet et al., 1995) and antagonized by LY393675 (Baker et al., 1998). Group II mGlu receptors may be activated by LY389795 (Monn et al., 1999), LY379268 (Monn et al., 1999), LY354740 (Schoepp et al., 1997; Wu et al., 1998), DCG-IV and 2R,4R-APDC (Schoepp et al., 1996), and antagonized by EGLU (4.3, Jane et al., 1996) and LY307452 (Wermuth et al., 1996; Escribano et al., 1998). Group III mGlu receptors may be activated by (RS)PPG (Gasparini et al., 1999a).

In addition to orthosteric ligands that directly interact with the glutamate recognition site, 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.

Nomenclature	mGlu1	mGlu2	mGlu3	mGlu4
Other names	mGluR1	mGluR2	mGluR3	mGluR4
Ensembl ID	ENSG00000152822	ENSG00000164082	ENSG00000105781	ENSG00000124493
Principal transduction	Gq/11	Gi/o	Gi/o	Gi/o
Selective agonists	–	–	NAAG (Wroblewska et al., 1997)	L-AP4, LSOP (Wu et al., 1998),
Selective positive allosteric modulators	Ro01-6128, Ro67-4853, Ro67-7476 (Knoflach et al., 2001)	LY487379 (Johnson et al., 2003), CBiPES (Johnson et al., 2005)	–	(−)-PHCCC (Maj et al., 2003), SIB1893, MPEP (Mathiesen et al., 2003), VU0155041 (Niswender et al., 2008)
Selective competitive antagonists	3-MATIDA (Moroni et al., 2002), AIDA (Moroni et al., 1997), (S)-(+)-CBPG (Mannaioni et al., 1999), LY367385 (Clark et al., 1997), (S)-TBPG (Costantino et al., 2001)	PCCG-4 (Pellicciari et al., 1996)	–	MAP4
Selective negative allosteric modulators	CPCCOEt (Litschig et al., 1999), BAY36-7620 (Carroll et al., 2001), LY456236 (Li et al., 2002), 3,5-DMPPP (Micheli et al., 2003), EM-TBPC (Malherbe et al., 2003), JNJ16259685 (Lavreysen et al., 2004)	–	–	–

Nomenclature	mGlu5	mGlu6	mGlu7	mGlu8
Other names	mGluR5	mGluR6	mGluR7	mGluR8
Ensembl ID	ENSG00000168959	ENSG00000113262	ENSG00000168160	ENSG00000179603
Principal transduction	Gq/11	Gi/o	Gi/o	Gi/o
Selective agonists	CHPG (Doherty et al., 1997), (S)-(+)-CBPG (Mannaioni et al., 1999)	Homo-AMPA (Bräuner-Osborne et al., 1996), 1-benzyl-APDC (Tuckmantel et al., 1997)	LSOP (Wu et al., 1998), L-AP4	LSOP (Wu et al., 1998), L-AP4, (S)-3,4-DCPG (Thomas et al., 2001)
Selective positive allosteric modulators	DFB (O'Brien et al., 2003), CPPHA (O'Brien et al., 2004), CDPPB (Kinney et al., 2005)	–	AMN082 (Flor et al., 2005)	–
Selective competitive antagonists	ACDPP (6.5, Bonnefous et al., 2005)	MAP4, THPG (Thoreson et al., 1997)	–	MPPG (Wu et al., 1998)
Selective negative allosteric modulators	SIB1757 (Varney et al., 1999), SIB1893 (Varney et al., 1999), MPEP (Gasparini et al., 1999b), MTEP (Brodkin et al., 2002), fenobam (Porter et al., 2005), YM298198 (Kohara et al., 2005)	–	MMPIP (Suzuki et al., 2007)	–

Radioligand binding using a variety of radioligands has been conducted on recombinant receptors (e.g. [³H]-R214127 (Lavreysen et al., 2003) and [³H]-YM298198 (Kohara et al., 2005) at mGlu₁ receptors and [³H]-methoxy-MPEP (Gasparini et al., 2002) and [³H]-methoxymethyl-MTEP (Anderson et al., 2002) 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 vs. 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 (Uyama et al., 1997). A potential novel mGlu 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 mGlu receptors), but resistant to LY341495 (Chung et al., 1997). There are also reports of a novel mGlu receptor coupled to phospholipase D in rat brain, which does not readily fit into the current classification (Pellegrini-Giampietro et al., 1996; Klein et al., 1997).

Glossary

Abbreviations:

[¹¹C]-JNJ-16567083

(3-ethyl-2-[¹¹C]methyl-6-quinolinyl)(cis-4-methoxycyclohexyl) methanone;

(RS)PPG

(R,S)-4-phosphonophenylglycine

(S)-(+)-CBPG

(s)-(1)-2-(39-carboxybicycle[1.1.1]pentyl)glycine

(S)-3,4-DCPG

(S)-3,4-dicarboxylphenylglycine

1S,3R-ACPD

1-aminocyclopentane-1S,3R-dicarboxylate

2R,4R-APDC

aminopyrrolidine-2R,4R-dicarboxylate; also known as LY314593

3-MATIDA

α-amino-5-carboxy-3-methyl-2-thiopheneacetic acid

3HPG

3-hydroxyphenylglycine

4CPG

4-carboxyphenylglycine

AIDA

1-aminoindan-1,5(RS)-dicarboxylic acid; also known as UPF523

AMN082

N,N'-bis(diphenylmethyl)-1,2-ethanediamine dihydrochloride

BAY 36-7620

(3aS,6aS)-6a-naphtalan-2-ylmethyl-5-methyliden-hexahyrol-cyclopenta[c]furan-1-one

CBiPES

N-[4′-cyano-biphenyl-3-yl]-N-(3-pyridinylmethyl)-ethanesulphonamide hydrochloride

CDPPB

3-cyano-N-(1,3-diphenyl-1H-[pyrazol-5-yl)benzamide

CHPG

2-chloro-5-hydroxyphenylglycine

CPCCOEt

cyclopropan[b]chromen-1a-carboxylate

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

DFB

3,3′-difluorobenzaldazine

DHPG

S-3,5-dihydroxyphenylglycine

DMPPP

3,5-dimethyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-tri-methyl-propyl) ester

EGLU

(s)-α-ethylglutamate

fenobam

N-(3-chlorophenyl)-N′-(4,5-dihydrol-1-methyl-4-oxo-1-H-imidazole-2-yl)-urea

JNJ16259685

(3,4-dihydro-2H-pyrano[2,3]b-quinolinyl-7-yl)(cis-4-methoxycyclohexyl)methanone

L-AP4

S-2-amino-4-phosphonobutyrate

L-CCG-I

(2S,3S,4S)α-(carboxycyclopropyl)glycine

LY307452

2S,4S-2-amino-4-(4,4-diphenylbut-1-yl)pentan-1,5-dioc acid

LY341495

2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl)-3-(xanth-9-yl)propanoic acid

LY354740

(+)-2-aminobicyclic[3.1.0]hexane-2,6-dicarboxylate

LY367385

(+)-2-methyl-4-carboxyphenylglycine

LY379268

(−)-2-oxa-4-aminobicylco[3.1.0]hexane-4,6-dicarboxylic acid

LY389795

(−)-2-thia-4-aminobicyclo[3.1.0]hexane-4,6-dicarboxylic acid

LY393675

α-substituted-cyclobutylglycine

LY456066

(2-[4-(indan-2-ylamino)-5,6,7,8-tetrahydro-quinazolin-2-ylsulfanyl]-ethanol,hydrochloride

LY456236

[(4-methoxy-phenyl)-(6-methoxy-quinazolin-4-yl)-amine hydrochloride

LY487379

2,2,2-trifluoro-N-[4-(2-methoxyphenoxy)phenyl]-N-(3-pyridinylmethyl)-ethanesulphonamide

MAP4

(S)-2-methyl-2-amino-4-phosphonobutanoate

methoxy-MPEP

2-methyl-6-((3-methoxyphenyl)ethynyl)-pyridine

methoxy-PEPy

3-methoxy-5-(pyridin-2-yl-ethynyl)-pyridine

methoxymethyl-MTEP

3-(methoxymethyl)-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine

MMPIP

6-(4-methoxyphenyl)-5-methyl-3-(4-pyridinyl)-isoxazolo[ 4,5-c]pyridin-4(5H)-one hydrochloride

MPEP

2-methyl-6-(phenylethynyl)-pyridine

MPPG

(RS)-α-methyl-4-phosphonophenylglycine

MTEP

3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine

NAAG

N-acetylaspartylglutamate, also known as spaglumic acid

PCCG-4

(2S,1'S,2'S,3′R)-2-(2′-carboxy-3′-phenylcyclopropyl)glycine

PHCCC

N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide

R214127

1-(3,4-dihydro-2H-pyrano[2,3-b]quinolin-7-yl)-2-phenyl-1-ethanone

Ro01-6128

diphenylacetyl-carbamic acid ethyl ester

Ro67-4853

(9H-xanthene-9-carbonyl)-carbamic acid butyl ester

Ro67-7476

(S)-2-(4-fluoro-phenyl)-1-(toluene-4-sulphonyl)-pyrrolidine

S-TBPG

2-(3′-(1H-tetrazol-5-yl)bicyclo[1.1.1]pent-1-yl)glycine

SIB1757

6-methyl-2-(phenylazo)-3-pyrindol

SIB1893

([phenylazo]-3-pyrindole)-2-methyl-6-(2-phenylethenyl)pyridine

THPG

(RS)-3,4,5-trihydroxyphenylglycine

VU0155041

cis-2-[[(3,5-dichlorophenyl)amino]carbonyl]cyclohexanec arboxylic acid

YM298198

(6-{[(2-methoxyethyl)amino]methyl}-N-methyl-N-neopentylthiaolo[3,2-a]benzoimidazole-2-carboxamide

Further Reading

D'Antoni S, Berretta A, Bonaccorso CM, Bruno V, Aronica E, Nicoletti F et al. (2008). Metabotropic glutamate receptors in glial cells. Neurochem Res33: 2436–2443.

Durand D, Pampillo M, Caruso C, Lasaga M (2008). Role of metabotropic glutamate receptors in the control of neuroendocrine function. Neuropharmacology55: 577–583.

Gerber U, Gee CE, Benquet P (2007). Metabotropic glutamate receptors: intracellular signaling pathways. Curr Opin Pharmacol7: 56–61.

Goudet C, Magnaghi V, Landry M, Nagy F, Gereau RW, Pin JP (2009). Metabotropic receptors for glutamate and GABA in pain. Brain Res Rev60: 43–56.

Kim CH, Lee J, Lee JY, Roche KW (2008). Metabotropic glutamate receptors: phosphorylation and receptor signaling. J Neurosci Res86: 1–10.

Krivoy A, Fischel T, Weizman A (2008). The possible involvement of metabotropic glutamate receptors in schizophrenia. Eur Neuropsychopharmacol18: 395–405.

Palucha A, Pilc A (2007). Metabotropic glutamate receptor ligands as possible anxiolytic and antidepressant drugs. Pharmacol Ther115: 116–147.

Pilc A, Chaki S, Nowak G, Witkin JM (2008). Mood disorders: regulation by metabotropic glutamate receptors. Biochem Pharmacol75: 997–1006.

Schkeryantz JM, Kingston AE, Johnson MP (2007). Prospects for metabotropic glutamate 1 receptor antagonists in the treatment of neuropathic pain. J Med Chem50: 2563–2568.

Schoepp DD, Alexander SP, Beart P, Conn PJ, Lodge D, Nakanishi S et al. (2000). Metabotropic glutamate receptors. In: Watson SP, Girdlestone D (eds). IUPHAR Compendium of Receptor Characterization and Classification, 2nd edn. IUPHAR Press: London, pp. 195–208.

Shin SS, Martino JJ, Chen S (2008). Metabotropic glutamate receptors (mGlus) and cellular transformation. Neuropharmacology55: 396–402.

Tang FR, Bradford HF, Ling EA (2009). Metabotropic glutamate receptors in the control of neuronal activity and as targets for development of anti-epileptogenic drugs. Curr Med Chem16: 2189–2204.

Wieronska JM, Pilc A (2009). Metabotropic glutamate receptors in the tripartite synapse as a target for new psychotropic drugs. Neurochem Int55: 85–97.