Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT6H8DE0)

• DOT Name: 5-hydroxytryptamine receptor 2C (HTR2C)
• Synonyms: 5-HT-2C; 5-HT2C; 5-HTR2C; 5-hydroxytryptamine receptor 1C; 5-HT-1C; 5-HT1C; Serotonin receptor 2C
• Gene Name: HTR2C
• UniProt ID: 5HT2C_HUMAN
• PDB ID: 6BQG; 6BQH; 8DPF; 8DPG; 8DPH; 8DPI
• Pfam ID: PF00001
• Sequence:
  MVNLRNAVHSFLVHLIGLLVWQSDISVSPVAAIVTDIFNTSDGGRFKFPDGVQNWPALSI
  VIIIIMTIGGNILVIMAVSMEKKLHNATNYFLMSLAIADMLVGLLVMPLSLLAILYDYVW
  PLPRYLCPVWISLDVLFSTASIMHLCAISLDRYVAIRNPIEHSRFNSRTKAIMKIAIVWA
  ISIGVSVPIPVIGLRDEEKVFVNNTTCVLNDPNFVLIGSFVAFFIPLTIMVITYCLTIYV
  LRRQALMLLHGHTEEPPGLSLDFLKCCKRNTAEEENSANPNQDQNARRRKKKERRPRGTM
  QAINNERKASKVLGIVFFVFLIMWCPFFITNILSVLCEKSCNQKLMEKLLNVFVWIGYVC
  SGINPLVYTLFNKIYRRAFSNYLRCNYKVEKKPPVRQIPRVAATALSGRELNVNIYRHTN
  EPVIEKASDNEPGIEMQVENLELPVNPSSVVSERISSV
• Function: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-iodophenyl-2-aminopropane (DOI) and lysergic acid diethylamide (LSD). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of down-stream effectors. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling activates a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and down-stream signaling cascades and promotes the release of Ca(2+) ions from intracellular stores. Regulates neuronal activity via the activation of short transient receptor potential calcium channels in the brain, and thereby modulates the activation of pro-opiomelacortin neurons and the release of CRH that then regulates the release of corticosterone. Plays a role in the regulation of appetite and eating behavior, responses to anxiogenic stimuli and stress. Plays a role in insulin sensitivity and glucose homeostasis.
• Tissue Specificity: Detected in brain.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  Neuroactive ligand-receptor interaction (hsa04080)
  Gap junction (hsa04540)
  Serotonergic sy.pse (hsa04726)
  Inflammatory mediator regulation of TRP channels (hsa04750)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  Serotonin receptors (R-HSA-390666)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	5-hydroxytryptamine receptor 2C (HTR2C) affects the response to substance of Clozapine.	[19]
Olanzapine	DMPFN6Y	Approved	5-hydroxytryptamine receptor 2C (HTR2C) increases the response to substance of Olanzapine.	[20]
Risperidone	DMN6DXL	Approved	5-hydroxytryptamine receptor 2C (HTR2C) increases the response to substance of Risperidone.	[21]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[1]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[2]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[3]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[5]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[6]
Nortriptyline	DM4KDYJ	Approved	Nortriptyline decreases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[8]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[9]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of 5-hydroxytryptamine receptor 2C (HTR2C).	[10]
SB 206553	DMS0QEP	Terminated	SB 206553 increases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[7]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of 5-hydroxytryptamine receptor 2C (HTR2C).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Fluoxetine	DM3PD2C	Approved	Fluoxetine affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[7]
Nefazodone	DM4ZS8M	Approved	Nefazodone affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[7]
Clomipramine	DMINRKW	Approved	Clomipramine affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[7]
Citalopram	DM2G9AE	Approved	Citalopram affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[7]
Trazodone	DMK1GBJ	Approved	Trazodone affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[7]
Fenfluramine	DM0762O	Phase 3	Fenfluramine affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[11]
Agomelatine	DMXYA5K	Withdrawn from market	Agomelatine affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[13]
LE-300	DMGJL16	Preclinical	LE-300 affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[14]
Fluphenazine	DMIT8LX	Investigative	Fluphenazine affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[17]
norfluoxetine	DMKNUP3	Investigative	norfluoxetine affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[7]
Racemic DOI	DM39FSQ	Investigative	Racemic DOI affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[18]
norfenfluramine	DMGI4ZW	Investigative	norfenfluramine affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[11]
MESULERGINE	DMKGWAH	Investigative	MESULERGINE affects the binding of 5-hydroxytryptamine receptor 2C (HTR2C).	[7]

2 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 affects the methylation of 5-hydroxytryptamine receptor 2C (HTR2C).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of 5-hydroxytryptamine receptor 2C (HTR2C).	[15]

References

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• [7] Inverse agonist and neutral antagonist actions of antidepressants at recombinant and native 5-hydroxytryptamine2C receptors: differential modulatio... Mol Pharmacol. 2008 Mar;73(3):748-57.
• [8] Downregulation of serotonin receptor subtypes by nortriptyline and adinazolam in major depressive disorder: neuroendocrine and platelet markers. Clin Neuropharmacol. 1993;16 Suppl 3:S19-31.
• [9] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [10] Characterization of the potent, selective Nrf2 activator, 3-(pyridin-3-ylsulfonyl)-5-(trifluoromethyl)-2H-chromen-2-one, in cellular and in vivo models of pulmonary oxidative stress. J Pharmacol Exp Ther. 2017 Oct;363(1):114-125.
• [11] Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000 Jan;57(1):75-81.
• [12] 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.
• [13] Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I). Eur J Med Chem. 2012 Mar;49:310-23.
• [14] Dopamine/serotonin receptor ligands. Part VIII: the dopamine receptor antagonist LE300 - modelled and X-ray structure plus further pharmacological characterization, including serotonin receptor binding, biogenic amine transporter testing and in vivo testings. Eur J Med Chem. 2004 Jun;39(6):481-9. doi: 10.1016/j.ejmech.2004.02.001.
• [15] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.
• [16] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [17] Discovery of antiandrogen activity of nonsteroidal scaffolds of marketed drugs. Proc Natl Acad Sci U S A. 2007 Jul 17;104(29):11927-32. doi: 10.1073/pnas.0609752104. Epub 2007 Jul 2.
• [18] A novel (benzodifuranyl)aminoalkane with extremely potent activity at the 5-HT2A receptor. J Med Chem. 1998 Dec 17;41(26):5148-9. doi: 10.1021/jm9803525.
• [19] HTR2C gene polymorphisms and the metabolic syndrome in patients with schizophrenia: a replication study. J Clin Psychopharmacol. 2009 Feb;29(1):16-20. doi: 10.1097/JCP.0b013e3181934462.
• [20] Olanzapine-induced weight gain is associated with the -759C/T and -697G/C polymorphisms of the HTR2C gene. Pharmacogenomics J. 2009 Aug;9(4):234-41. doi: 10.1038/tpj.2009.18. Epub 2009 May 12.
• [21] Pharmacogenetics of risperidone therapy in autism: association analysis of eight candidate genes with drug efficacy and adverse drug reactions. Pharmacogenomics J. 2010 Oct;10(5):418-30.