Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQBWN4U)

• DOT Name: Beta-1 adrenergic receptor (ADRB1)
• Synonyms: Beta-1 adrenoreceptor; Beta-1 adrenoceptor
• Gene Name: ADRB1
• UniProt ID: ADRB1_HUMAN
• PDB ID: 2LSQ; 7BTS; 7BU6; 7BU7; 7BVQ
• Pfam ID: PF00001
• Sequence:
  MGAGVLVLGASEPGNLSSAAPLPDGAATAARLLVPASPPASLLPPASESPEPLSQQWTAG
  MGLLMALIVLLIVAGNVLVIVAIAKTPRLQTLTNLFIMSLASADLVMGLLVVPFGATIVV
  WGRWEYGSFFCELWTSVDVLCVTASIETLCVIALDRYLAITSPFRYQSLLTRARARGLVC
  TVWAISALVSFLPILMHWWRAESDEARRCYNDPKCCDFVTNRAYAIASSVVSFYVPLCIM
  AFVYLRVFREAQKQVKKIDSCERRFLGGPARPPSPSPSPVPAPAPPPGPPRPAAAAATAP
  LANGRAGKRRPSRLVALREQKALKTLGIIMGVFTLCWLPFFLANVVKAFHRELVPDRLFV
  FFNWLGYANSAFNPIIYCRSPDFRKAFQGLLCCARRAARRRHATHGDRPRASGCLARPGP
  PPSPGAASDDDDDDVVGATPPARLLEPWAGCNGGAAADSDSSLDEPCRPGFASESKV
• Function: Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins. This receptor binds epinephrine and norepinephrine with approximately equal affinity. Mediates Ras activation through G(s)-alpha- and cAMP-mediated signaling. Involved in the regulation of sleep/wake behaviors.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  cAMP sig.ling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Gap junction (hsa04540)
  Regulation of lipolysis in adipocytes (hsa04923)
  Renin secretion (hsa04924)
  Salivary secretion (hsa04970)
  Chemical carcinogenesis - receptor activation (hsa05207)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Adrenoceptors (R-HSA-390696)

Molecular Interaction Atlas (MIA) of This DOT

This DOT Affected the Drug Response of 5 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Dobutamine	DMD1B8Z	Approved	Beta-1 adrenergic receptor (ADRB1) affects the response to substance of Dobutamine.	[19]
Angiotensin Ii	DMLWQ27	Approved	Beta-1 adrenergic receptor (ADRB1) increases the Myocardial disorders ADR of Angiotensin Ii.	[20]
Diltiazem	DMAI7ZV	Approved	Beta-1 adrenergic receptor (ADRB1) increases the response of Diltiazem.	[21]
Verapamil	DMA7PEW	Phase 2/3 Trial	Beta-1 adrenergic receptor (ADRB1) affects the response to substance of Verapamil.	[21]
Forskolin	DM6ITNG	Investigative	Beta-1 adrenergic receptor (ADRB1) affects the response to substance of Forskolin.	[22]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
[3H]cAMP	DMZRQU7	Investigative	Beta-1 adrenergic receptor (ADRB1) increases the abundance of [3H]cAMP.	[23]

3 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 Beta-1 adrenergic receptor (ADRB1).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Beta-1 adrenergic receptor (ADRB1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Beta-1 adrenergic receptor (ADRB1).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Beta-1 adrenergic receptor (ADRB1).	[2]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Beta-1 adrenergic receptor (ADRB1).	[3]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Beta-1 adrenergic receptor (ADRB1).	[4]
Demecolcine	DMCZQGK	Approved	Demecolcine decreases the expression of Beta-1 adrenergic receptor (ADRB1).	[5]
Nicotine	DMWX5CO	Approved	Nicotine increases the expression of Beta-1 adrenergic receptor (ADRB1).	[6]
Carvedilol	DMHTEAO	Approved	Carvedilol increases the activity of Beta-1 adrenergic receptor (ADRB1).	[7]
Labetalol	DMK8U72	Approved	Labetalol decreases the activity of Beta-1 adrenergic receptor (ADRB1).	[8]
Amiodarone	DMUTEX3	Phase 2/3 Trial	Amiodarone decreases the expression of Beta-1 adrenergic receptor (ADRB1).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Beta-1 adrenergic receptor (ADRB1).	[13]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Beta-1 adrenergic receptor (ADRB1).	[15]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Beta-1 adrenergic receptor (ADRB1).	[5]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Beta-1 adrenergic receptor (ADRB1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Vortioxetine	DM6F1PU	Approved	Vortioxetine affects the binding of Beta-1 adrenergic receptor (ADRB1).	[9]
Spermidine	DMVJNFI	Phase 3	Spermidine affects the binding of Beta-1 adrenergic receptor (ADRB1).	[10]
Spermine	DMD4BFY	Terminated	Spermine affects the binding of Beta-1 adrenergic receptor (ADRB1).	[10]
Cyanopindolol	DMIBLGH	Investigative	Cyanopindolol affects the binding of Beta-1 adrenergic receptor (ADRB1).	[17]
iodocyanopindolol	DMOA2J8	Investigative	iodocyanopindolol affects the binding of Beta-1 adrenergic receptor (ADRB1).	[18]

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] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [3] Analysis of estrogen agonism and antagonism of tamoxifen, raloxifene, and ICI182780 in endometrial cancer cells: a putative role for the epidermal growth factor receptor ligand amphiregulin. J Soc Gynecol Investig. 2005 Oct;12(7):e55-67.
• [4] Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
• [5] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [6] Nicotine promotes colon tumor growth and angiogenesis through beta-adrenergic activation. Toxicol Sci. 2007 Jun;97(2):279-87.
• [7] Agonist actions of "beta-blockers" provide evidence for two agonist activation sites or conformations of the human beta1-adrenoceptor. Mol Pharmacol. 2003 Jun;63(6):1312-21. doi: 10.1124/mol.63.6.1312.
• [8] Preclinical pharmacologic properties of dilevalol, an antihypertensive agent possessing selective beta 2 agonist-mediated vasodilation and beta antagonism. Am J Cardiol. 1989 Jun 5;63(19):3I-6I. doi: 10.1016/0002-9149(89)90120-3.
• [9] Discovery of 1-[2-(2,4-dimethylphenylsulfanyl)phenyl]piperazine (Lu AA21004): a novel multimodal compound for the treatment of major depressive disorder. J Med Chem. 2011 May 12;54(9):3206-21. doi: 10.1021/jm101459g. Epub 2011 Apr 12.
• [10] Functional effects of polyamines via activation of human 1- and 2-adrenoceptors stably expressed in CHO cells. Pharmacol Rep. 2010 Jul-Aug;62(4):696-706. doi: 10.1016/s1734-1140(10)70327-3.
• [11] Effects of chronic amiodarone treatment on human myocardial beta adrenoceptor density and adenylate cyclase response. Cardiovasc Res. 1991 Jun;25(6):503-9. doi: 10.1093/cvr/25.6.503.
• [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] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [14] 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.
• [15] 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.
• [16] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [17] Beta 1-adrenoceptor selectivity of nebivolol and bisoprolol. A comparison of [3H]CGP 12.177 and [125I]iodocyanopindolol binding studies. Eur J Pharmacol. 2003 Jan 26;460(1):19-26. doi: 10.1016/s0014-2999(02)02875-3.
• [18] Selective activation of beta3-adrenoceptors by octopamine: comparative studies in mammalian fat cells. Naunyn Schmiedebergs Arch Pharmacol. 1999 Apr;359(4):310-21. doi: 10.1007/pl00005357.
• [19] The Arg389Gly 1-adrenoceptor gene polymorphism influences the acute effects of -adrenoceptor blockade on contractility in the human heart. Clin Res Cardiol. 2011 Aug;100(8):641-7. doi: 10.1007/s00392-011-0288-1. Epub 2011 Feb 11.
• [20] 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.
• [21] A common 1-adrenergic receptor polymorphism predicts favorable response to rate-control therapy in atrial fibrillation. J Am Coll Cardiol. 2012 Jan 3;59(1):49-56. doi: 10.1016/j.jacc.2011.08.061.
• [22] Beta 1-adrenergic receptor polymorphisms confer differential function and predisposition to heart failure. Nat Med. 2003 Oct;9(10):1300-5. doi: 10.1038/nm930. Epub 2003 Sep 14.
• [23] Constitutive activity of the human beta(1)-adrenergic receptor in beta(1)-receptor transgenic mice. Mol Pharmacol. 2001 Oct;60(4):712-7.