Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTICZ1O)

• DTT Name: Metabotropic glutamate receptor 4 (mGluR4)
• Synonyms: mGluR4; Group III metabotropic glutamate receptor 4; GPRC1D
• Gene Name: GRM4
• DTT Type: Literature-reported target; [1]
• Related Disease: Parkinsonism [ICD-11: 8A00]
• BioChemical Class: GPCR glutamate
• UniProt ID: GRM4_HUMAN
• TTD ID: T99402
• Sequence:
  MPGKRGLGWWWARLPLCLLLSLYGPWMPSSLGKPKGHPHMNSIRIDGDITLGGLFPVHGR
  GSEGKPCGELKKEKGIHRLEAMLFALDRINNDPDLLPNITLGARILDTCSRDTHALEQSL
  TFVQALIEKDGTEVRCGSGGPPIITKPERVVGVIGASGSSVSIMVANILRLFKIPQISYA
  STAPDLSDNSRYDFFSRVVPSDTYQAQAMVDIVRALKWNYVSTVASEGSYGESGVEAFIQ
  KSREDGGVCIAQSVKIPREPKAGEFDKIIRRLLETSNARAVIIFANEDDIRRVLEAARRA
  NQTGHFFWMGSDSWGSKIAPVLHLEEVAEGAVTILPKRMSVRGFDRYFSSRTLDNNRRNI
  WFAEFWEDNFHCKLSRHALKKGSHVKKCTNRERIGQDSAYEQEGKVQFVIDAVYAMGHAL
  HAMHRDLCPGRVGLCPRMDPVDGTQLLKYIRNVNFSGIAGNPVTFNENGDAPGRYDIYQY
  QLRNDSAEYKVIGSWTDHLHLRIERMHWPGSGQQLPRSICSLPCQPGERKKTVKGMPCCW
  HCEPCTGYQYQVDRYTCKTCPYDMRPTENRTGCRPIPIIKLEWGSPWAVLPLFLAVVGIA
  ATLFVVITFVRYNDTPIVKASGRELSYVLLAGIFLCYATTFLMIAEPDLGTCSLRRIFLG
  LGMSISYAALLTKTNRIYRIFEQGKRSVSAPRFISPASQLAITFSLISLQLLGICVWFVV
  DPSHSVVDFQDQRTLDPRFARGVLKCDISDLSLICLLGYSMLLMVTCTVYAIKTRGVPET
  FNEAKPIGFTMYTTCIVWLAFIPIFFGTSQSADKLYIQTTTLTVSVSLSASVSLGMLYMP
  KVYIILFHPEQNVPKRKRSLKAVVTAATMSNKFTQKGNFRPNGEAKSELCENLEAPALAT
  KQTYVTYTNHAI
• Function: 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. G-protein coupled receptor for glutamate.
• KEGG Pathway:
  Neuroactive ligand-receptor interaction (hsa04080)
  Glutamatergic synapse (hsa04724)
  Taste transduction (hsa04742)
• Reactome Pathway:
  Class C/3 (Metabotropic glutamate/pheromone receptors) (R-HSA-420499)
  G alpha (i) signalling events (R-HSA-418594)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
DT-1687	DMU2GP4	Parkinson disease	8A00.0	Phase 2	[1]

27 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(2S,1'R,2'S)-2-(2'-phosphonocyclopropyl)glycine	DMLS29E	Discovery agent	N.A.	Investigative	[2]
(S)-3,4-DCPG	DMG5BUA	Discovery agent	N.A.	Investigative	[3]
2-methyl-6-(phenylethynyl)pyridine	DMVQK4Y	Discovery agent	N.A.	Investigative	[4]
ACPT-I	DM264XN	Discovery agent	N.A.	Investigative	[5]
ADX-88178	DM70H6P	Anxiety disorder	6B00-6B0Z	Investigative	[1]
CPPG	DMVHX5T	Discovery agent	N.A.	Investigative	[6]
FP0429	DMYBQN9	Discovery agent	N.A.	Investigative	[7]
L-AP4	DMPJFGI	Discovery agent	N.A.	Investigative	[6], [2]
L-CCG-I	DMPZ8XH	Discovery agent	N.A.	Investigative	[8]
L-serine-O-phosphate	DMTJ1NH	Discovery agent	N.A.	Investigative	[9]
LSP1-2111	DM74J10	Discovery agent	N.A.	Investigative	[10]
LSP4-2022	DMBWHGP	Discovery agent	N.A.	Investigative	[11]
Lu AF21934	DMH693E	Discovery agent	N.A.	Investigative	[12]
MAP4	DMUCE93	Discovery agent	N.A.	Investigative	[6]
MPPG	DMJHQ9T	Discovery agent	N.A.	Investigative	[6]
PHCCC	DMNJY79	Discovery agent	N.A.	Investigative	[13]
PMID20638279C11	DMFHS4V	Discovery agent	N.A.	Investigative	[14]
PMID20638279C7	DMKFJP2	Discovery agent	N.A.	Investigative	[14]
PMID21688779C22a	DMEBM19	Discovery agent	N.A.	Investigative	[15]
PMID22465637C1	DMV4ZWD	Discovery agent	N.A.	Investigative	[16]
VU0001171	DMDF2U3	Discovery agent	N.A.	Investigative	[17]
VU0092145	DMVMXKP	Discovery agent	N.A.	Investigative	[17]
VU0155041	DMPKSTD	Discovery agent	N.A.	Investigative	[18]
VU0359516	DM9V01W	Discovery agent	N.A.	Investigative	[19]
VU0361737	DME71ON	Discovery agent	N.A.	Investigative	[20]
VU0364770	DMXY980	Discovery agent	N.A.	Investigative	[21]
VU0400195	DM7L51U	Discovery agent	N.A.	Investigative	[22]

References

• [1] URL: 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).
• [2] Synthesis and preliminary pharmacological evaluation of the four stereoisomers of (2S)-2-(2'-phosphono-3'-phenylcyclopropyl)glycine, the first clas... Bioorg Med Chem. 2007 May 1;15(9):3161-70.
• [3] (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.
• [4] Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br J Pharmacol. 2003 Mar;138(6):1026-30.
• [5] Synthesis 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.
• [6] Ligand binding to the amino-terminal domain of the mGluR4 subtype of metabotropic glutamate receptor. J Biol Chem. 1999 Apr 9;274(15):10008-13.
• [7] Amino-pyrrolidine tricarboxylic acids give new insight into group III metabotropic glutamate receptor activation mechanism. Mol Pharmacol. 2007 Mar;71(3):704-12.
• [8] Agonist 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.
• [9] Serine-O-phosphate has affinity for type IV, but not type I, metabotropic glutamate receptor. Neuroreport. 1993 Sep;4(9):1099-101.
• [10] Electrophysiological 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.
• [11] A 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.
• [12] Synergy 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.
• [13] (-)-PHCCC, a positive allosteric modulator of mGluR4: characterization, mechanism of action, and neuroprotection. Neuropharmacology. 2003 Dec;45(7):895-906.
• [14] An 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.
• [15] Tricyclic thiazolopyrazole derivatives as metabotropic glutamate receptor 4 positive allosteric modulators. J Med Chem. 2011 Jul 28;54(14):5070-81.
• [16] 4-(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.
• [17] Positive 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.
• [18] Discovery, characterization, and antiparkinsonian effect of novel positive allosteric modulators of metabotropic glutamate receptor 4. Mol Pharmacol. 2008 Nov;74(5):1345-58.
• [19] Re-exploration of the PHCCC Scaffold: Discovery of Improved Positive Allosteric Modulators of mGluR4. ACS Chem Neurosci. 2010 Jun 16;1(6):411-419.
• [20] Synthesis 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.
• [21] The 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.
• [22] Discovery, 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.