Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTM1AD9J)

• DOT Name: 5-hydroxytryptamine receptor 2B (HTR2B)
• Synonyms: 5-HT-2B; 5-HT2B; Serotonin receptor 2B
• Gene Name: HTR2B
• UniProt ID: 5HT2B_HUMAN
• PDB ID: 4IB4; 4NC3; 5TUD; 5TVN; 6DRX; 6DRY; 6DRZ; 6DS0; 7SRQ; 7SRR; 7SRS
• Pfam ID: PF00001
• Sequence:
  MALSYRVSELQSTIPEHILQSTFVHVISSNWSGLQTESIPEEMKQIVEEQGNKLHWAALL
  ILMVIIPTIGGNTLVILAVSLEKKLQYATNYFLMSLAVADLLVGLFVMPIALLTIMFEAM
  WPLPLVLCPAWLFLDVLFSTASIMHLCAISVDRYIAIKKPIQANQYNSRATAFIKITVVW
  LISIGIAIPVPIKGIETDVDNPNNITCVLTKERFGDFMLFGSLAAFFTPLAIMIVTYFLT
  IHALQKKAYLVKNKPPQRLTWLTVSTVFQRDETPCSSPEKVAMLDGSRKDKALPNSGDET
  LMRRTSTIGKKSVQTISNEQRASKVLGIVFFLFLLMWCPFFITNITLVLCDSCNQTTLQM
  LLEIFVWIGYVSSGVNPLVYTLFNKTFRDAFGRYITCNYRATKSVKTLRKRSSKIYFRNP
  MAENSKFFKKHGIRNGINPAMYQSPMRLRSSTIQSSSIILLDTLLLTENEGDKTEEQVSY
  V
• Function: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances. 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. Plays a role in the regulation of dopamine and 5-hydroxytryptamine release, 5-hydroxytryptamine uptake and in the regulation of extracellular dopamine and 5-hydroxytryptamine levels, and thereby affects neural activity. May play a role in the perception of pain. Plays a role in the regulation of behavior, including impulsive behavior. Required for normal proliferation of embryonic cardiac myocytes and normal heart development. Protects cardiomyocytes against apoptosis. Plays a role in the adaptation of pulmonary arteries to chronic hypoxia. Plays a role in vasoconstriction. Required for normal osteoblast function and proliferation, and for maintaining normal bone density. Required for normal proliferation of the interstitial cells of Cajal in the intestine.
• Tissue Specificity: Ubiquitous. Detected in liver, kidney, heart, pulmonary artery, and intestine. Detected at lower levels in blood, placenta and brain, especially in cerebellum, occipital cortex and frontal cortex.
• 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 2 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gabapentin	DM6T924	Approved	5-hydroxytryptamine receptor 2B (HTR2B) increases the Sleep disturbances (incl subtypes) ADR of Gabapentin.	[16]
Fenfluramine	DM0762O	Phase 3	5-hydroxytryptamine receptor 2B (HTR2B) increases the response to substance of Fenfluramine.	[17]

This DOT Affected the Regulation of Drug Effects of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
D-myo-inositol 1,4,5-trisphosphate	DMNUKIX	Investigative	5-hydroxytryptamine receptor 2B (HTR2B) decreases the abundance of D-myo-inositol 1,4,5-trisphosphate.	[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 2B (HTR2B).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of 5-hydroxytryptamine receptor 2B (HTR2B).	[9]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 5-hydroxytryptamine receptor 2B (HTR2B).	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[2]
Progesterone	DMUY35B	Approved	Progesterone decreases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[4]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[5]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[6]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[7]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[8]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[12]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[13]
Hexadecanoic acid	DMWUXDZ	Investigative	Hexadecanoic acid increases the expression of 5-hydroxytryptamine receptor 2B (HTR2B).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Marinol	DM70IK5	Approved	Marinol affects the binding of 5-hydroxytryptamine receptor 2B (HTR2B).	[3]
LYSERGIC ACID DIETHYLAMIDE	DMACMLO	Withdrawn from market	LYSERGIC ACID DIETHYLAMIDE affects the binding of 5-hydroxytryptamine receptor 2B (HTR2B).	[10]
Serotonin	DMOFCRY	Investigative	Serotonin affects the binding of 5-hydroxytryptamine receptor 2B (HTR2B).	[15]

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] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [3] Evaluation of first generation synthetic cannabinoids on binding at non-cannabinoid receptors and in a battery of in?vivo assays in mice. Neuropharmacology. 2016 Nov;110(Pt A):143-153. doi: 10.1016/j.neuropharm.2016.07.016. Epub 2016 Jul 20.
• [4] Effects of progesterone treatment on expression of genes involved in uterine quiescence. Reprod Sci. 2011 Aug;18(8):781-97.
• [5] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [6] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [7] Mifepristone induced progesterone withdrawal reveals novel regulatory pathways in human endometrium. Mol Hum Reprod. 2007 Sep;13(9):641-54.
• [8] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [9] 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.
• [10] Pharmacokinetic and pharmacodynamic evaluation of 5-methoxy-2-aminoindane (MEAI): A new binge-mitigating agent. Toxicol Appl Pharmacol. 2018 Mar 15;343:29-39. doi: 10.1016/j.taap.2018.02.009. Epub 2018 Feb 16.
• [11] 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.
• [12] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [13] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.
• [14] 5-HT 2 receptor mediates high-fat diet-induced hepatic steatosis and very low density lipoprotein overproduction in rats. Obes Res Clin Pract. 2018 Jan-Feb;12(Suppl 2):16-28. doi: 10.1016/j.orcp.2016.03.015. Epub 2016 Apr 28.
• [15] 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.
• [16] ADReCS-Target: target profiles for aiding drug safety research and application. Nucleic Acids Res. 2018 Jan 4;46(D1):D911-D917. doi: 10.1093/nar/gkx899.
• [17] Serotonin 5-HT(2B) receptor loss of function mutation in a patient with fenfluramine-associated primary pulmonary hypertension. Cardiovasc Res. 2003 Dec 1;60(3):518-28. doi: 10.1016/j.cardiores.2003.09.015.
• [18] The natural mutation encoding a C terminus-truncated 5-hydroxytryptamine 2B receptor is a gain of proliferative functions. Mol Pharmacol. 2005 Apr;67(4):983-91. doi: 10.1124/mol.104.008268. Epub 2004 Dec 29.