Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT7GF3AI)

• DOT Name: Histamine H3 receptor (HRH3)
• Synonyms: H3R; HH3R; G-protein coupled receptor 97
• Gene Name: HRH3
• UniProt ID: HRH3_HUMAN
• PDB ID: 7F61
• Pfam ID: PF00001
• Sequence:
  MERAPPDGPLNASGALAGEAAAAGGARGFSAAWTAVLAALMALLIVATVLGNALVMLAFV
  ADSSLRTQNNFFLLNLAISDFLVGAFCIPLYVPYVLTGRWTFGRGLCKLWLVVDYLLCTS
  SAFNIVLISYDRFLSVTRAVSYRAQQGDTRRAVRKMLLVWVLAFLLYGPAILSWEYLSGG
  SSIPEGHCYAEFFYNWYFLITASTLEFFTPFLSVTFFNLSIYLNIQRRTRLRLDGAREAA
  GPEPPPEAQPSPPPPPGCWGCWQKGHGEAMPLHRYGVGEAAVGAEAGEATLGGGGGGGSV
  ASPTSSSGSSSRGTERPRSLKRGSKPSASSASLEKRMKMVSQSFTQRFRLSRDRKVAKSL
  AVIVSIFGLCWAPYTLLMIIRAACHGHCVPDYWYETSFWLLWANSAVNPVLYPLCHHSFR
  RAFTKLLCPQKLKIQPHSSLEHCWK
• Function: The H3 subclass of histamine receptors could mediate the histamine signals in CNS and peripheral nervous system. Signals through the inhibition of adenylate cyclase and displays high constitutive activity (spontaneous activity in the absence of agonist). Agonist stimulation of isoform 3 neither modified adenylate cyclase activity nor induced intracellular calcium mobilization.
• Tissue Specificity: Expressed predominantly in the CNS, with the greatest expression in the thalamus and caudate nucleus. The various isoforms are mainly coexpressed in brain, but their relative expression level varies in a region-specific manner. Isoform 3 and isoform 7 are highly expressed in the thalamus, caudate nucleus and cerebellum while isoform 5 and isoform 6 show a poor expression. Isoform 5 and isoform 6 show a high expression in the amygdala, substantia nigra, cerebral cortex and hypothalamus. Isoform 7 is not found in hypothalamus or substantia nigra.
• KEGG Pathway: Neuroactive ligand-receptor interaction (hsa04080)
• Reactome Pathway: Histamine receptors (R-HSA-390650)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Histamine H3 receptor (HRH3).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Histamine H3 receptor (HRH3).	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Histamine H3 receptor (HRH3).	[2]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Histamine H3 receptor (HRH3).	[5]

4 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Irdabisant	DMR3E4L	Phase 1	Irdabisant affects the binding of Histamine H3 receptor (HRH3).	[4]
Guanosine-5'-Triphosphate	DMV2OJX	Investigative	Guanosine-5'-Triphosphate affects the binding of Histamine H3 receptor (HRH3).	[4]
Clobenpropit	DM537OH	Investigative	Clobenpropit affects the binding of Histamine H3 receptor (HRH3).	[6]
N-[3H]alpha-methylhistamine	DMWDCV1	Investigative	N-[3H]alpha-methylhistamine affects the binding of Histamine H3 receptor (HRH3).	[7]

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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] 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.
• [4] Discovery and characterization of 6-{4-[3-(R)-2-methylpyrrolidin-1-yl)propoxy]phenyl}-2H-pyridazin-3-one (CEP-26401, irdabisant): a potent, selective histamine H3 receptor inverse agonist. J Med Chem. 2011 Jul 14;54(13):4781-92. doi: 10.1021/jm200401v. Epub 2011 Jun 2.
• [5] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.
• [6] Molecular determinants of ligand binding modes in the histamine H(4) receptor: linking ligand-based three-dimensional quantitative structure-activity relationship (3D-QSAR) models to in silico guided receptor mutagenesis studies. J Med Chem. 2011 Dec 8;54(23):8136-47. doi: 10.1021/jm201042n. Epub 2011 Nov 7.
• [7] Discovery of two clinical histamine H(3) receptor antagonists: trans-N-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidinylmethyl)phenyl]cyclobutanecarboxamide (PF-03654746) and trans-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-ylmethyl)phenyl]-N-(2-methylpropyl)cyclobutanecarboxamide (PF-03654764). J Med Chem. 2011 Nov 10;54(21):7602-20. doi: 10.1021/jm200939b. Epub 2011 Oct 7.