Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT38K9MK)

• DOT Name: 5-hydroxytryptamine receptor 1A (HTR1A)
• Synonyms: 5-HT-1A; 5-HT1A; G-21; Serotonin receptor 1A
• Gene Name: HTR1A
• Related Disease: Menstrual cycle-dependent periodic fever
• UniProt ID: 5HT1A_HUMAN
• PDB ID: 7E2X; 7E2Y; 7E2Z; 8JSP; 8W8B
• Pfam ID: PF00001
• Sequence:
  MDVLSPGQGNNTTSPPAPFETGGNTTGISDVTVSYQVITSLLLGTLIFCAVLGNACVVAA
  IALERSLQNVANYLIGSLAVTDLMVSVLVLPMAALYQVLNKWTLGQVTCDLFIALDVLCC
  TSSILHLCAIALDRYWAITDPIDYVNKRTPRRAAALISLTWLIGFLISIPPMLGWRTPED
  RSDPDACTISKDHGYTIYSTFGAFYIPLLLMLVLYGRIFRAARFRIRKTVKKVEKTGADT
  RHGASPAPQPKKSVNGESGSRNWRLGVESKAGGALCANGAVRQGDDGAALEVIEVHRVGN
  SKEHLPLPSEAGPTPCAPASFERKNERNAEAKRKMALARERKTVKTLGIIMGTFILCWLP
  FFIVALVLPFCESSCHMPTLLGAIINWLGYSNSLLNPVIYAYFNKDFQNAFKKIIKCKFC
  RQ
• Function: G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs 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, such as adenylate cyclase. Beta-arrestin family members inhibit signaling via G proteins and mediate activation of alternative signaling pathways. Signaling inhibits adenylate cyclase activity and activates a phosphatidylinositol-calcium second messenger system that regulates the release of Ca(2+) ions from intracellular stores. Plays a role in the regulation of 5-hydroxytryptamine release and in the regulation of dopamine and 5-hydroxytryptamine metabolism. Plays a role in the regulation of dopamine and 5-hydroxytryptamine levels in the brain, and thereby affects neural activity, mood and behavior. Plays a role in the response to anxiogenic stimuli.
• Tissue Specificity: Detected in lymph nodes, thymus and spleen. Detected in activated T-cells, but not in resting T-cells.
• KEGG Pathway:
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Serotonergic sy.pse (hsa04726)
  Taste transduction (hsa04742)
• Reactome Pathway: Serotonin receptors (R-HSA-390666)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Menstrual cycle-dependent periodic fever	DISCFGN2	Limited	Autosomal dominant	[1]

This DOT Affected the Drug Response of 4 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Methamphetamine	DMPM4SK	Approved	5-hydroxytryptamine receptor 1A (HTR1A) increases the response to substance of Methamphetamine.	[9]
Fluoxetine	DM3PD2C	Approved	5-hydroxytryptamine receptor 1A (HTR1A) increases the response to substance of Fluoxetine.	[10]
Olanzapine	DMPFN6Y	Approved	5-hydroxytryptamine receptor 1A (HTR1A) increases the response of Olanzapine.	[11]
Perospirone	DMVHJLX	Approved	5-hydroxytryptamine receptor 1A (HTR1A) increases the response of Perospirone.	[11]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Nefazodone	DM4ZS8M	Approved	Nefazodone affects the binding of 5-hydroxytryptamine receptor 1A (HTR1A).	[2]
Trazodone	DMK1GBJ	Approved	Trazodone affects the binding of 5-hydroxytryptamine receptor 1A (HTR1A).	[2]
Etoperidone	DMR7U8F	Phase 4	Etoperidone affects the binding of 5-hydroxytryptamine receptor 1A (HTR1A).	[2]
DU 125530	DM63UA9	Discontinued in Phase 2	DU 125530 affects the binding of 5-hydroxytryptamine receptor 1A (HTR1A).	[5]
WB-4101	DMQU8B1	Terminated	WB-4101 affects the binding of 5-hydroxytryptamine receptor 1A (HTR1A).	[6]
WAY-100635	DMG58FX	Terminated	WAY-100635 affects the binding of 5-hydroxytryptamine receptor 1A (HTR1A).	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate decreases the activity of 5-hydroxytryptamine receptor 1A (HTR1A).	[3]
THAPSIGARGIN	DMDMQIE	Preclinical	THAPSIGARGIN increases the activity of 5-hydroxytryptamine receptor 1A (HTR1A).	[3]

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 increases the methylation of 5-hydroxytryptamine receptor 1A (HTR1A).	[4]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of 5-hydroxytryptamine receptor 1A (HTR1A).	[8]

References

• [1] Classification of Genes: Standardized Clinical Validity Assessment of Gene-Disease Associations Aids Diagnostic Exome Analysis and Reclassifications. Hum Mutat. 2017 May;38(5):600-608. doi: 10.1002/humu.23183. Epub 2017 Feb 13.
• [2] Binding of antidepressants to human brain receptors: focus on newer generation compounds. Psychopharmacology (Berl). 1994 May;114(4):559-65. doi: 10.1007/BF02244985.
• [3] Mechanisms of regulation of agonist efficacy at the 5-HT(1A) receptor by phospholipid-derived signaling components. J Pharmacol Exp Ther. 2001 Jun;297(3):1025-35.
• [4] 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.
• [5] 5-Hydroxytryptamine1A receptor occupancy by novel full antagonist 2-[4-[4-(7-chloro-2,3-dihydro-1,4-benzdioxyn-5-yl)-1-piperazinyl]butyl]-1,2-benzisothiazol-3-(2H)-one-1,1-dioxide: a[11C][O-methyl-3H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride (WAY-100635) positron emission tomography study in humans. J Pharmacol Exp Ther. 2002 Jun;301(3):1144-50.
• [6] Antagonism by neuroleptics of serotonin 5-HT1A and 5-HT2 receptors of normal human brain in vitro. Eur J Pharmacol. 1987 Nov 10;143(2):279-82. doi: 10.1016/0014-2999(87)90544-9.
• [7] Design, synthesis, radiolabeling, and in vitro and in vivo evaluation of bridgehead iodinated analogues of N-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}-N-(pyridin-2-yl)cyclohexanecarboxamide (WAY-100635) as potential SPECT ligands for the 5-HT1A receptor. J Med Chem. 2011 May 26;54(10):3480-91. doi: 10.1021/jm1009956. Epub 2011 Apr 26.
• [8] Bisphenol A Represses Dopaminergic Neuron Differentiation from Human Embryonic Stem Cells through Downregulating the Expression of Insulin-like Growth Factor 1. Mol Neurobiol. 2017 Jul;54(5):3798-3812. doi: 10.1007/s12035-016-9898-y. Epub 2016 Jun 7.
• [9] Serotonin 1A receptor gene is associated with Japanese methamphetamine-induced psychosis patients. Neuropharmacology. 2010 Feb;58(2):452-6. doi: 10.1016/j.neuropharm.2009.09.006. Epub 2009 Sep 10.
• [10] Response to fluoxetine and serotonin 1A receptor (C-1019G) polymorphism in Taiwan Chinese major depressive disorder. Pharmacogenomics J. 2006 Jan-Feb;6(1):27-33. doi: 10.1038/sj.tpj.6500340.
• [11] Serotonin-1A receptor gene polymorphism and the ability of antipsychotic drugs to improve attention in schizophrenia. Adv Ther. 2010 May;27(5):307-13. doi: 10.1007/s12325-010-0035-4. Epub 2010 Jun 8.