Target Information

Target General Infomation
Target ID
T99402
Former ID
TTDR00965
Target Name
Metabotropic glutamate receptor 4
Gene Name
GRM4
Synonyms
Group III metabotropic glutamate receptor 4; mGluR4; GRM4
Target Type
Research
Disease Anxiety disorder [ICD9: 300, 311; ICD10: F32, F40-F42]
Neurological disease [ICD9: 338, 338.2, 410, 782.3,780; ICD10: I21, I22, R52, R52.1-R52.2, R60.9, G89]
Function
G-protein coupled receptor for glutamate. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Signaling inhibits adenylate cyclase activity.
BioChemical Class
GPCR glutamate
Target Validation
T99402
UniProt ID
Q14833
Sequence
MPGKRGLGWWWARLPLCLLLSLYGPWMPSSLGKPKGHPHMNSIRIDGDITLGGLFPVHGR
GSEGKPCGELKKEKGIHRLEAMLFALDRINNDPDLLPNITLGARILDTCSRDTHALEQSL
TFVQALIEKDGTEVRCGSGGPPIITKPERVVGVIGASGSSVSIMVANILRLFKIPQISYA
STAPDLSDNSRYDFFSRVVPSDTYQAQAMVDIVRALKWNYVSTVASEGSYGESGVEAFIQ
KSREDGGVCIAQSVKIPREPKAGEFDKIIRRLLETSNARAVIIFANEDDIRRVLEAARRA
NQTGHFFWMGSDSWGSKIAPVLHLEEVAEGAVTILPKRMSVRGFDRYFSSRTLDNNRRNI
WFAEFWEDNFHCKLSRHALKKGSHVKKCTNRERIGQDSAYEQEGKVQFVIDAVYAMGHAL
HAMHRDLCPGRVGLCPRMDPVDGTQLLKYIRNVNFSGIAGNPVTFNENGDAPGRYDIYQY
QLRNDSAEYKVIGSWTDHLHLRIERMHWPGSGQQLPRSICSLPCQPGERKKTVKGMPCCW
HCEPCTGYQYQVDRYTCKTCPYDMRPTENRTGCRPIPIIKLEWGSPWAVLPLFLAVVGIA
ATLFVVITFVRYNDTPIVKASGRELSYVLLAGIFLCYATTFLMIAEPDLGTCSLRRIFLG
LGMSISYAALLTKTNRIYRIFEQGKRSVSAPRFISPASQLAITFSLISLQLLGICVWFVV
DPSHSVVDFQDQRTLDPRFARGVLKCDISDLSLICLLGYSMLLMVTCTVYAIKTRGVPET
FNEAKPIGFTMYTTCIVWLAFIPIFFGTSQSADKLYIQTTTLTVSVSLSASVSLGMLYMP
KVYIILFHPEQNVPKRKRSLKAVVTAATMSNKFTQKGNFRPNGEAKSELCENLEAPALAT
KQTYVTYTNHAI
Inhibitor (2S,1'R,2'S)-2-(2'-phosphonocyclopropyl)glycine Drug Info [528723]
GLUTAMATE Drug Info [528723]
L-1-amino-4-phosphonobutanoic acid Drug Info [528723]
Agonist (S)-3,4-DCPG Drug Info [525960]
ACPT-I Drug Info [534471]
FP0429 Drug Info [528577]
L-AP4 Drug Info [525456]
L-CCG-I Drug Info [526752]
L-serine-O-phosphate Drug Info [533900]
LSP1-2111 Drug Info [530212]
LSP4-2022 Drug Info [531757]
[3H]AP4 Drug Info [525456]
Modulator ADX-88178 Drug Info [543749]
DT-1687 Drug Info [543749]
Modulator (allosteric modulator) compound 1 Drug Info [531863]
compound 11 Drug Info [531039]
compound 22a Drug Info [531523]
compound 7 Drug Info [531039]
Lu AF21934 Drug Info [531872]
MPEP Drug Info [526594]
PHCCC Drug Info [526858]
VU0001171 Drug Info [529883]
VU0092145 Drug Info [529883]
VU0155041 Drug Info [529617]
VU0359516 Drug Info [530991]
VU0361737 Drug Info [530167]
VU0364770 Drug Info [531700]
VU0400195 Drug Info [531644]
Antagonist CPPG Drug Info [525456]
MAP4 Drug Info [525456]
MPPG Drug Info [525456]
Pathways
KEGG Pathway Neuroactive ligand-receptor interaction
Glutamatergic synapse
Taste transduction
PANTHER Pathway Heterotrimeric G-protein signaling pathway-Gi alpha and Gs alpha mediated pathway
Heterotrimeric G-protein signaling pathway-Gq alpha and Go alpha mediated pathway
Metabotropic glutamate receptor group III pathway
Reactome G alpha (i) signalling events
Class C/3 (Metabotropic glutamate/pheromone receptors)
WikiPathways GPCRs, Class C Metabotropic glutamate, pheromone
GPCR ligand binding
GPCR downstream signaling
References
Ref 525456Ligand binding to the amino-terminal domain of the mGluR4 subtype of metabotropic glutamate receptor. J Biol Chem. 1999 Apr 9;274(15):10008-13.
Ref 525960(S)-3,4-DCPG, a potent and selective mGlu8a receptor agonist, activates metabotropic glutamate receptors on primary afferent terminals in the neonatal rat spinal cord. Neuropharmacology. 2001 Mar;40(3):311-8.
Ref 526594Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br J Pharmacol. 2003 Mar;138(6):1026-30.
Ref 526752Agonist analysis of 2-(carboxycyclopropyl)glycine isomers for cloned metabotropic glutamate receptor subtypes expressed in Chinese hamster ovary cells. Br J Pharmacol. 1992 Oct;107(2):539-43.
Ref 526858(-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology. 2003 Dec;45(7):895-906.
Ref 528577Amino-pyrrolidine tricarboxylic acids give new insight into group III metabotropic glutamate receptor activation mechanism. Mol Pharmacol. 2007 Mar;71(3):704-12. Epub 2006 Dec 13.
Ref 528723Bioorg Med Chem. 2007 May 1;15(9):3161-70. Epub 2007 Feb 22.Synthesis and preliminary pharmacological evaluation of the four stereoisomers of (2S)-2-(2'-phosphono-3'-phenylcyclopropyl)glycine, the first class of 3'-substituted trans C1'-2'-2-(2'-phosphonocyclopropyl)glycines.
Ref 529617Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol. 2008 Nov;74(5):1345-58.
Ref 529883Positive allosteric modulators of the metabotropic glutamate receptor subtype 4 (mGluR4). Part II: Challenges in hit-to-lead. Bioorg Med Chem Lett. 2009 Feb 1;19(3):962-6.
Ref 530167Synthesis and evaluation of a series of heterobiarylamides that are centrally penetrant metabotropic glutamate receptor 4 (mGluR4) positive allosteric modulators (PAMs). J Med Chem. 2009 Jul 23;52(14):4115-8.
Ref 530212Electrophysiological and behavioral evidence that modulation of metabotropic glutamate receptor 4 with a new agonist reverses experimental parkinsonism. FASEB J. 2009 Oct;23(10):3619-28.
Ref 530991Re-exploration of the PHCCC Scaffold: Discovery of Improved Positive Allosteric Modulators of mGluR4. ACS Chem Neurosci. 2010 Jun 16;1(6):411-419.
Ref 531039An orally bioavailable positive allosteric modulator of the mGlu4 receptor with efficacy in an animal model of motor dysfunction. Bioorg Med Chem Lett. 2010 Aug 15;20(16):4901-5.
Ref 531523Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators. J Med Chem. 2011 Jul 28;54(14):5070-81.
Ref 531644Discovery, synthesis, and structure-activity relationship development of a series of N-4-(2,5-dioxopyrrolidin-1-yl)phenylpicolinamides (VU0400195, ML182): characterization of a novel positive allosteric modulator of the metabotropic glutamate receptor 4 (mGlu(4)) with oral efficacy in an antiparkinsonian animal model. J Med Chem. 2011 Nov 10;54(21):7639-47.
Ref 531700The metabotropic glutamate receptor 4-positive allosteric modulator VU0364770 produces efficacy alone and in combination with L-DOPA or an adenosine 2A antagonist in preclinical rodent models of Parkinson's disease. J Pharmacol Exp Ther. 2012 Feb;340(2):404-21.
Ref 531757A novel selective metabotropic glutamate receptor 4 agonist reveals new possibilities for developing subtype selective ligands with therapeutic potential. FASEB J. 2012 Apr;26(4):1682-93.
Ref 5318634-(1-Phenyl-1H-pyrazol-4-yl)quinolines as novel, selective and brain penetrant metabotropic glutamate receptor 4 positive allosteric modulators. Bioorg Med Chem Lett. 2012 May 1;22(9):3235-9.
Ref 531872Synergy between L-DOPA and a novel positive allosteric modulator of metabotropic glutamate receptor 4: implications for Parkinson's disease treatment and dyskinesia. Neuropharmacology. 2013 Mar;66:158-69.
Ref 533900Serine-O-phosphate has affinity for type IV, but not type I, metabotropic glutamate receptor. Neuroreport. 1993 Sep;4(9):1099-101.
Ref 534471Synthesis and pharmacological characterization of aminocyclopentanetricarboxylic acids: new tools to discriminate between metabotropic glutamate receptor subtypes. J Med Chem. 1997 Sep 12;40(19):3119-29.
Ref 543749(http://www.guidetopharmacology.org/) Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 292).

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