Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT8A9EF)

• DTT Name: Metabotropic glutamate receptor 3 (mGluR3)
• Synonyms: mGLUR3; Group III metabotropic glutamate receptor; GPRC1C
• Gene Name: GRM3
• DTT Type: Clinical trial target; [1]
• Related Disease: Schizophrenia [ICD-11: 6A20]
• BioChemical Class: GPCR glutamate
• UniProt ID: GRM3_HUMAN
• TTD ID: T02719
• Sequence:
  MKMLTRLQVLTLALFSKGFLLSLGDHNFLRREIKIEGDLVLGGLFPINEKGTGTEECGRI
  NEDRGIQRLEAMLFAIDEINKDDYLLPGVKLGVHILDTCSRDTYALEQSLEFVRASLTKV
  DEAEYMCPDGSYAIQENIPLLIAGVIGGSYSSVSIQVANLLRLFQIPQISYASTSAKLSD
  KSRYDYFARTVPPDFYQAKAMAEILRFFNWTYVSTVASEGDYGETGIEAFEQEARLRNIC
  IATAEKVGRSNIRKSYDSVIRELLQKPNARVVVLFMRSDDSRELIAAASRANASFTWVAS
  DGWGAQESIIKGSEHVAYGAITLELASQPVRQFDRYFQSLNPYNNHRNPWFRDFWEQKFQ
  CSLQNKRNHRRVCDKHLAIDSSNYEQESKIMFVVNAVYAMAHALHKMQRTLCPNTTKLCD
  AMKILDGKKLYKDYLLKINFTAPFNPNKDADSIVKFDTFGDGMGRYNVFNFQNVGGKYSY
  LKVGHWAETLSLDVNSIHWSRNSVPTSQCSDPCAPNEMKNMQPGDVCCWICIPCEPYEYL
  ADEFTCMDCGSGQWPTADLTGCYDLPEDYIRWEDAWAIGPVTIACLGFMCTCMVVTVFIK
  HNNTPLVKASGRELCYILLFGVGLSYCMTFFFIAKPSPVICALRRLGLGSSFAICYSALL
  TKTNCIARIFDGVKNGAQRPKFISPSSQVFICLGLILVQIVMVSVWLILEAPGTRRYTLA
  EKRETVILKCNVKDSSMLISLTYDVILVILCTVYAFKTRKCPENFNEAKFIGFTMYTTCI
  IWLAFLPIFYVTSSDYRVQTTTMCISVSLSGFVVLGCLFAPKVHIILFQPQKNVVTHRLH
  LNRFSVSGTGTTYSQSSASTYVPTVCNGREVLDSTTSSL
• 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)
  Cocaine addiction (hsa05030)
• 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

7 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY404039	DMWZIRJ	Schizophrenia	6A20	Phase 3	[1], [2], [3]
MP-101	DMYCITZ	Alzheimer disease	8A20	Phase 2	[4]
Oleoyl-estrone	DM0RA8F	Alzheimer disease	8A20	Phase 2	[5], [6]
RO-4995819	DMNTC7O	Major depressive disorder	6A70.3	Phase 2	[7]
BCI-632	DMZYCWT	Alzheimer disease	8A20	Phase 1	[8], [9]
BCI-838	DMRXDN3	Major depressive disorder	6A70.3	Phase 1	[10]
Pomaglumetad	DMTOLI5	Schizophrenia	6A20	Phase 1	[11]

4 Patented Agent(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
PMID25435285-Compound-15	DMHBWNS	N. A.	N. A.	Patented	[12]
PMID25435285-Compound-16	DMKFX2G	N. A.	N. A.	Patented	[12]
PMID25435285-Compound-20	DMG9FYH	N. A.	N. A.	Patented	[12]
PMID25435285-Compound-22	DM27U1F	N. A.	N. A.	Patented	[12]

3 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
LY-544344	DMSC4K1	Anxiety disorder	6B00-6B0Z	Discontinued in Phase 3	[13]
LY354740	DM08BIZ	Anxiety disorder	6B00-6B0Z	Discontinued in Phase 2	[14], [15], [16]
R-1578	DMAPRGQ	Mood disorder	6A60-6E23	Discontinued in Phase 2	[17]

14 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+)-MCPG	DMG5QJB	Discovery agent	N.A.	Investigative	[18]
(1S,3R)-ACPD	DM5DOAF	Discovery agent	N.A.	Investigative	[18]
eGlu	DMKW0Q3	Discovery agent	N.A.	Investigative	[19]
L-CCG-I	DMPZ8XH	Discovery agent	N.A.	Investigative	[18]
LY-379268	DMME40U	Discovery agent	N.A.	Investigative	[20]
LY-389795	DM6Y2XG	Discovery agent	N.A.	Investigative	[20]
MNI-135	DMBJFH9	Discovery agent	N.A.	Investigative	[21]
MNI-136	DM5C9VI	Discovery agent	N.A.	Investigative	[21]
MNI-137	DMKRI1J	Discovery agent	N.A.	Investigative	[21]
NAAG	DMFGOW0	Discovery agent	N.A.	Investigative	[19]
Ro4491533	DMJLSX0	Discovery agent	N.A.	Investigative	[22]
VU0463597	DM96FQ2	Discovery agent	N.A.	Investigative	[23]
[3H]LY341495	DMGX0Y8	Discovery agent	N.A.	Investigative	[19]
[3H]quisqualate	DMDQBTX	Discovery agent	N.A.	Investigative	[24]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Schizophrenia	6A20	Pre-frontal cortex	6.89E-02	-0.39	-0.17
Schizophrenia	6A20	Superior temporal cortex	4.60E-02	-0.05	-0.15
Major depressive disorder	6A20	Pre-frontal cortex	6.03E-01	0.07	0.22

References

• [1] Positive allosteric modulators of the metabotropic glutamate receptor 2 for the treatment of schizophrenia. Expert Opin Ther Pat. 2009 Sep;19(9):1259-75.
• [2] Glutamate and dopamine components in schizophrenia. J Psychiatry Neurosci. 2009 Mar;34(2):143-9.
• [3] Glutamate receptor mGlu2 and mGlu3 knockout striata are dopamine supersensitive, with elevated D2(High) receptors and marked supersensitivity to the dopamine agonist (+)PHNO. Synapse. 2009 Mar;63(3):247-51.
• [4] ClinicalTrials.gov (NCT03044249) A Study of MP-101 in Dementia-Related Psychosis and/or Agitation and Aggression. U.S. National Institutes of Health.
• [5] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [6] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [7] Novel glutamatergic drugs for the treatment of mood disorders. Neuropsychiatr Dis Treat. 2013; 9: 1101-1112.
• [8] Synthesis, in vitro pharmacology, structure-activity relationships, and pharmacokinetics of 3-alkoxy-2-amino-6-fluorobicyclo[3.1.0]hexane-2,6-dicarboxylic acid derivatives as potent and selective group II metabotropic glutamate receptor antagonists. J Med Chem. 2004 Aug 26;47(18):4570-87.
• [9] Interpreting expression profiles of cancers by genome-wide survey of breadth of expression in normal tissues. Genomics 2005 Aug;86(2):127-41.
• [10] Metabotropic glutamate receptor subtype 2 (GRM2; MGLUR2); GRM3 (MGLUR3). SciBX 3(13); doi:10.1038/scibx.2010.413. April 1 2010
• [11] LY-2140023, a prodrug of the group II metabotropic glutamate receptor agonist LY-404039 for the potential treatment of schizophrenia. Curr Opin Investig Drugs. 2010 Jul;11(7):833-45.
• [12] Novel metabotropic glutamate receptor 2/3 antagonists and their therapeutic applications: a patent review (2005 - present).Expert Opin Ther Pat. 2015 Jan;25(1):69-90.
• [13] Glutamate- and GABA-based CNS therapeutics. Curr Opin Pharmacol. 2006 Feb;6(1):7-17.
• [14] Mutagenesis and molecular modeling of the orthosteric binding site of the mGlu2 receptor determining interactions of the group II receptor antagonist (3)H-HYDIA. ChemMedChem. 2009 Jul;4(7):1086-94.
• [15] Effects of a metabotropic glutamate receptor group II agonist LY354740 in animal models of positive schizophrenia symptoms and cognition. Behav Pharmacol. 2009 Feb;20(1):56-66.
• [16] Modulation of group II metabotropic glutamate receptor (mGlu2) elicits common changes in rat and mice sleep-wake architecture. Eur J Pharmacol. 2009 Jan 28;603(1-3):62-72.
• [17] Clinical pipeline report, company report or official report of Roche.
• [18] [3H]-LY341495 as a novel antagonist radioligand for group II metabotropic glutamate (mGlu) receptors: characterization of binding to membranes of mGlu receptor subtype expressing cells. Neuropharmacology. 1999 Oct;38(10):1519-29.
• [19] Characterization of [(3)H]-LY354740 binding to rat mGlu2 and mGlu3 receptors expressed in CHO cells using semliki forest virus vectors. Neuropharmacology. 2000 Jul 24;39(10):1700-6.
• [20] Synthesis and metabotropic glutamate receptor activity of S-oxidized variants of (-)-4-amino-2-thiabicyclo-[3.1.0]hexane-4,6-dicarboxylate: identif... J Med Chem. 2007 Jan 25;50(2):233-40.
• [21] A novel family of potent negative allosteric modulators of group II metabotropic glutamate receptors. J Pharmacol Exp Ther. 2007 Jul;322(1):254-64.
• [22] Synthesis and characterization of 1,3-dihydro-benzo[b][1,4]diazepin-2-one derivatives: Part 4. In vivo active potent and selective non-competitive metabotropic glutamate receptor 2/3 antagonists. Bioorg Med Chem Lett. 2010 Dec 1;20(23):6969-74.
• [23] Development of a novel, CNS-penetrant, metabotropic glutamate receptor 3 (mGlu3) NAM probe (ML289) derived from a closely related mGlu5 PAM. Bioorg Med Chem Lett. 2012 Jun 15;22(12):3921-5.
• [24] Excitatory amino acid receptor ligands: resolution, absolute stereochemistry, and enantiopharmacology of 2-amino-3-(4-butyl-3-hydroxyisoxazol-5-yl)... J Med Chem. 1998 Mar 12;41(6):930-9.