Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL2VFIV)

• DOT Name: N-arachidonyl glycine receptor (GPR18)
• Synonyms: NAGly receptor; G-protein coupled receptor 18
• Gene Name: GPR18
• UniProt ID: GPR18_HUMAN
• Pfam ID: PF00001
• Sequence:
  MITLNNQDQPVPFNSSHPDEYKIAALVFYSCIFIIGLFVNITALWVFSCTTKKRTTVTIY
  MMNVALVDLIFIMTLPFRMFYYAKDEWPFGEYFCQILGALTVFYPSIALWLLAFISADRY
  MAIVQPKYAKELKNTCKAVLACVGVWIMTLTTTTPLLLLYKDPDKDSTPATCLKISDIIY
  LKAVNVLNLTRLTFFFLIPLFIMIGCYLVIIHNLLHGRTSKLKPKVKEKSIRIIITLLVQ
  VLVCFMPFHICFAFLMLGTGENSYNPWGAFTTFLMNLSTCLDVILYYIVSKQFQARVISV
  MLYRNYLRSMRRKSFRSGSLRSLSNINSEML
• Function: Receptor for endocannabinoid N-arachidonyl glycine (NAGly). However, conflicting results about the role of NAGly as an agonist are reported. Can also be activated by plant-derived and synthetic cannabinoid agonists. The activity of this receptor is mediated by G proteins which inhibit adenylyl cyclase. May contribute to regulation of the immune system. Is required for normal homeostasis of CD8+ subsets of intraepithelial lymphocytes (IELs) (CD8alphaalpha and CD8alphabeta IELs)in small intstine by supporting preferential migration of CD8alphaalpha T-cells to intraepithelial compartment over lamina propria compartment, and by mediating their reconstitution into small intestine after bone marrow transplant. Plays a role in hypotensive responses, mediating reduction in intraocular and blood pressure. Mediates NAGly-induced process of reorganization of actin filaments and induction of acrosomal exocytosis.
• Tissue Specificity: Expressed in midpiece of spermatozoon (at protein level) . Most abundant in testis and spleen . Highly expressed in CD4 and CD8-positive T-cells as well as CD19-positive B-cells .
• Reactome Pathway:
  G alpha (i) signalling events (R-HSA-418594)
  Class A/1 (Rhodopsin-like receptors) (R-HSA-373076)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of N-arachidonyl glycine receptor (GPR18).	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of N-arachidonyl glycine receptor (GPR18).	[2]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of N-arachidonyl glycine receptor (GPR18).	[3]
Cyclophosphamide	DM4O2Z7	Approved	Cyclophosphamide decreases the expression of N-arachidonyl glycine receptor (GPR18).	[4]
Lindane	DMB8CNL	Approved	Lindane increases the expression of N-arachidonyl glycine receptor (GPR18).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of N-arachidonyl glycine receptor (GPR18).	[4]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of N-arachidonyl glycine receptor (GPR18).	[5]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of N-arachidonyl glycine receptor (GPR18).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of N-arachidonyl glycine receptor (GPR18).	[7]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A decreases the expression of N-arachidonyl glycine receptor (GPR18).	[4]
Chlorpyrifos	DMKPUI6	Investigative	Chlorpyrifos increases the expression of N-arachidonyl glycine receptor (GPR18).	[8]
Rapamycin Immunosuppressant Drug	DM678IB	Investigative	Rapamycin Immunosuppressant Drug increases the expression of N-arachidonyl glycine receptor (GPR18).	[4]

References

• [1] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Toxicogenomics-based identification of mechanisms for direct immunotoxicity. Toxicol Sci. 2013 Oct;135(2):328-46.
• [4] Transcriptome-based functional classifiers for direct immunotoxicity. Arch Toxicol. 2014 Mar;88(3):673-89.
• [5] Highly active combination of BRD4 antagonist and histone deacetylase inhibitor against human acute myelogenous leukemia cells. Mol Cancer Ther. 2014 May;13(5):1142-54.
• [6] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.
• [7] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [8] Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro. J Appl Toxicol. 2015 Jul;35(7):831-41.