Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTWXJX0M)

• DOT Name: 5-hydroxytryptamine receptor 2A (HTR2A)
• Synonyms: 5-HT-2; 5-HT-2A; Serotonin receptor 2A
• Gene Name: HTR2A
• UniProt ID: 5HT2A_HUMAN
• PDB ID: 6A93; 6A94; 6WGT; 6WH4; 6WHA; 7RAN; 7VOD; 7VOE; 7WC4; 7WC5; 7WC6; 7WC7; 7WC8; 7WC9
• Pfam ID: PF00001
• Sequence:
  MDILCEENTSLSSTTNSLMQLNDDTRLYSNDFNSGEANTSDAFNWTVDSENRTNLSCEGC
  LSPSCLSLLHLQEKNWSALLTAVVIILTIAGNILVIMAVSLEKKLQNATNYFLMSLAIAD
  MLLGFLVMPVSMLTILYGYRWPLPSKLCAVWIYLDVLFSTASIMHLCAISLDRYVAIQNP
  IHHSRFNSRTKAFLKIIAVWTISVGISMPIPVFGLQDDSKVFKEGSCLLADDNFVLIGSF
  VSFFIPLTIMVITYFLTIKSLQKEATLCVSDLGTRAKLASFSFLPQSSLSSEKLFQRSIH
  REPGSYTGRRTMQSISNEQKACKVLGIVFFLFVVMWCPFFITNIMAVICKESCNEDVIGA
  LLNVFVWIGYLSSAVNPLVYTLFNKTYRSAFSRYIQCQYKENKKPLQLILVNTIPALAYK
  SSQLQMGQKKNSKQDAKTTDNDCSMVALGKQHSEEASKDNSDGVNEKVSCV
• Function: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 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 phospholipase C and a phosphatidylinositol-calcium second messenger system that modulates the activity of phosphatidylinositol 3-kinase and promotes the release of Ca(2+) ions from intracellular stores. Affects neural activity, perception, cognition and mood. Plays a role in the regulation of behavior, including responses to anxiogenic situations and psychoactive substances. Plays a role in intestinal smooth muscle contraction, and may play a role in arterial vasoconstriction; (Microbial infection) Acts as a receptor for human JC polyomavirus/JCPyV.
• Tissue Specificity: Detected in brain cortex (at protein level). Detected in blood platelets.
• 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 12 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Clozapine	DMFC71L	Approved	5-hydroxytryptamine receptor 2A (HTR2A) increases the response to substance of Clozapine.	[18]
Citalopram	DM2G9AE	Approved	5-hydroxytryptamine receptor 2A (HTR2A) increases the response of Citalopram.	[19]
Gabapentin	DM6T924	Approved	5-hydroxytryptamine receptor 2A (HTR2A) increases the Sleep disturbances (incl subtypes) ADR of Gabapentin.	[20]
Paroxetine	DM5PVQE	Approved	5-hydroxytryptamine receptor 2A (HTR2A) affects the response to substance of Paroxetine.	[21]
Risperidone	DMN6DXL	Approved	5-hydroxytryptamine receptor 2A (HTR2A) increases the response to substance of Risperidone.	[18]
Aripiprazole	DM3NUMH	Approved	5-hydroxytryptamine receptor 2A (HTR2A) decreases the response to substance of Aripiprazole.	[18]
Luvox	DMJKROX	Approved	5-hydroxytryptamine receptor 2A (HTR2A) affects the response to substance of Luvox.	[22]
TRYPTAMINE	DMAFPHB	Phase 3	5-hydroxytryptamine receptor 2A (HTR2A) decreases the response to substance of TRYPTAMINE.	[18]
Serotonin	DMOFCRY	Investigative	5-hydroxytryptamine receptor 2A (HTR2A) decreases the response to substance of Serotonin.	[18]
Racemic DOI	DM39FSQ	Investigative	5-hydroxytryptamine receptor 2A (HTR2A) decreases the response to substance of Racemic DOI.	[18]
2-(1H-indol-3-yl)-N,N-dimethylethanamine	DMR9Q4Y	Investigative	5-hydroxytryptamine receptor 2A (HTR2A) decreases the response to substance of 2-(1H-indol-3-yl)-N,N-dimethylethanamine.	[18]
m-chlorophenylpiperazine	DMM1J2D	Investigative	5-hydroxytryptamine receptor 2A (HTR2A) increases the response to substance of m-chlorophenylpiperazine.	[18]

3 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 5-hydroxytryptamine receptor 2A (HTR2A).	[1]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of 5-hydroxytryptamine receptor 2A (HTR2A).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 5-hydroxytryptamine receptor 2A (HTR2A).	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of 5-hydroxytryptamine receptor 2A (HTR2A).	[2]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of 5-hydroxytryptamine receptor 2A (HTR2A).	[4]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of 5-hydroxytryptamine receptor 2A (HTR2A).	[5]
Ketanserin	DMVLMW6	Approved	Ketanserin decreases the activity of 5-hydroxytryptamine receptor 2A (HTR2A).	[8]
Bardoxolone methyl	DMODA2X	Phase 3	Bardoxolone methyl decreases the activity of 5-hydroxytryptamine receptor 2A (HTR2A).	[9]
N-DESMETHYLCLOZAPINE	DMVIRN3	Phase 2	N-DESMETHYLCLOZAPINE decreases the expression of 5-hydroxytryptamine receptor 2A (HTR2A).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of 5-hydroxytryptamine receptor 2A (HTR2A).	[13]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of 5-hydroxytryptamine receptor 2A (HTR2A).	[14]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride decreases the expression of 5-hydroxytryptamine receptor 2A (HTR2A).	[15]
Tributylstannanyl	DMHN7CB	Investigative	Tributylstannanyl decreases the expression of 5-hydroxytryptamine receptor 2A (HTR2A).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Haloperidol	DM96SE0	Approved	Haloperidol affects the binding of 5-hydroxytryptamine receptor 2A (HTR2A).	[6]
Olanzapine	DMPFN6Y	Approved	Olanzapine affects the binding of 5-hydroxytryptamine receptor 2A (HTR2A).	[7]
Paliperidone	DM7NPJS	Approved	Paliperidone affects the binding of 5-hydroxytryptamine receptor 2A (HTR2A).	[6]
Fenfluramine	DM0762O	Phase 3	Fenfluramine affects the binding of 5-hydroxytryptamine receptor 2A (HTR2A).	[10]
Fluphenazine	DMIT8LX	Investigative	Fluphenazine affects the binding of 5-hydroxytryptamine receptor 2A (HTR2A).	[17]
norfenfluramine	DMGI4ZW	Investigative	norfenfluramine affects the binding of 5-hydroxytryptamine receptor 2A (HTR2A).	[10]

References

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• [7] No evidence for binding of clozapine, olanzapine and/or haloperidol to selected receptors involved in body weight regulation. Pharmacogenomics J. 2007 Aug;7(4):275-81. doi: 10.1038/sj.tpj.6500418. Epub 2006 Sep 19.
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• [10] Possible role of valvular serotonin 5-HT(2B) receptors in the cardiopathy associated with fenfluramine. Mol Pharmacol. 2000 Jan;57(1):75-81.
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• [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.
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• [16] Tributyltin role on the serotonin and histamine receptors in human umbilical artery. Toxicol In Vitro. 2018 Aug;50:210-216. doi: 10.1016/j.tiv.2018.03.006. Epub 2018 Mar 24.
• [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] Pharmacologic analysis of non-synonymous coding h5-HT2A SNPs reveals alterations in atypical antipsychotic and agonist efficacies. Pharmacogenomics J. 2006 Jan-Feb;6(1):42-51. doi: 10.1038/sj.tpj.6500342.
• [19] Variation in the gene encoding the serotonin 2A receptor is associated with outcome of antidepressant treatment. Am J Hum Genet. 2006 May;78(5):804-814. doi: 10.1086/503820. Epub 2006 Mar 20.
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• [21] Prediction of response to paroxetine and venlafaxine by serotonin-related genes in obsessive-compulsive disorder in a randomized, double-blind trial. J Clin Psychiatry. 2007 May;68(5):747-53. doi: 10.4088/jcp.v68n0512.
• [22] [Serotonin 2A receptor gene polymorphism and clinical efficacy of fluvoxamine in children with autistic disorder]. No To Hattatsu. 2003 Jan;35(1):23-8.