Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPR99C7)

• DOT Name: G-protein coupled receptor 52 (GPR52)
• Gene Name: GPR52
• Related Disease:
  Huntington disease
  Psychotic disorder
  Schizophrenia
  Intellectual disability
  Mental disorder
• UniProt ID: GPR52_HUMAN
• PDB ID: 6LI0; 6LI1; 6LI2; 6LI3; 8HMP
• Pfam ID: PF00001
• Sequence:
  MNESRWTEWRILNMSSGIVNVSERHSCPLGFGHYSVVDVCIFETVVIVLLTFLIIAGNLT
  VIFVFHCAPLLHHYTTSYFIQTMAYADLFVGVSCLVPTLSLLHYSTGVHESLTCQVFGYI
  ISVLKSVSMACLACISVDRYLAITKPLSYNQLVTPCRLRICIILIWIYSCLIFLPSFFGW
  GKPGYHGDIFEWCATSWLTSAYFTGFIVCLLYAPAAFVVCFTYFHIFKICRQHTKEINDR
  RARFPSHEVDSSRETGHSPDRRYAMVLFRITSVFYMLWLPYIIYFLLESSRVLDNPTLSF
  LTTWLAISNSFCNCVIYSLSNSVFRLGLRRLSETMCTSCMCVKDQEAQEPKPRKRANSCS
  I
• Function: Gs-coupled receptor activated by antipsychotics reserpine leading to an increase in intracellular cAMP and its internalization. May play a role in locomotor activity through modulation of dopamine, NMDA and ADORA2A-induced locomotor activity. These behavioral changes are accompanied by modulation of the dopamine receptor signaling pathway in striatum. Modulates HTT level via cAMP-dependent but PKA independent mechanisms throught activation of RAB39B that translocates HTT to the endoplasmic reticulum, thus avoiding proteasome degradation.
• Tissue Specificity: Expressed in brain, especially in striatum.

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Huntington disease	DISQPLA4	Strong	Genetic Variation	[1]
Psychotic disorder	DIS4UQOT	Strong	Biomarker	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Intellectual disability	DISMBNXP	Disputed	Biomarker	[4]
Mental disorder	DIS3J5R8	Limited	Biomarker	[5]

1 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of G-protein coupled receptor 52 (GPR52).	[6]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of G-protein coupled receptor 52 (GPR52).	[7]

References

• [1] Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease-associated phenotypes.Brain. 2018 Jun 1;141(6):1782-1798. doi: 10.1093/brain/awy081.
• [2] Design and synthesis of 1-(1-benzothiophen-7-yl)-1H-pyrazole, a novel series of G protein-coupled receptor 52 (GPR52) agonists.Bioorg Med Chem. 2018 May 1;26(8):1598-1608. doi: 10.1016/j.bmc.2018.02.005. Epub 2018 Feb 10.
• [3] FTBMT, a Novel and Selective GPR52 Agonist, Demonstrates Antipsychotic-Like and Procognitive Effects in Rodents, Revealing a Potential Therapeutic Agent for Schizophrenia.J Pharmacol Exp Ther. 2017 Nov;363(2):253-264. doi: 10.1124/jpet.117.242925. Epub 2017 Aug 29.
• [4] Array-based molecular karyotyping in fetal brain malformations: Identification of novel candidate genes and chromosomal regions.Birth Defects Res A Clin Mol Teratol. 2016 Jan;106(1):16-26. doi: 10.1002/bdra.23458. Epub 2015 Dec 17.
• [5] Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists.Bioorg Med Chem. 2017 Jun 15;25(12):3098-3115. doi: 10.1016/j.bmc.2017.03.064. Epub 2017 Apr 1.
• [6] MS4A3-HSP27 target pathway reveals potential for haematopoietic disorder treatment in alimentary toxic aleukia. Cell Biol Toxicol. 2023 Feb;39(1):201-216. doi: 10.1007/s10565-021-09639-4. Epub 2021 Sep 28.
• [7] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.