Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTW2CD1O)

• DOT Name: Alpha-1D adrenergic receptor (ADRA1D)
• Synonyms: Alpha-1A adrenergic receptor; Alpha-1D adrenoreceptor; Alpha-1D adrenoceptor; Alpha-adrenergic receptor 1a
• Gene Name: ADRA1D
• UniProt ID: ADA1D_HUMAN
• Pfam ID: PF00001
• Sequence:
  MTFRDLLSVSFEGPRPDSSAGGSSAGGGGGSAGGAAPSEGPAVGGVPGGAGGGGGVVGAG
  SGEDNRSSAGEPGSAGAGGDVNGTAAVGGLVVSAQGVGVGVFLAAFILMAVAGNLLVILS
  VACNRHLQTVTNYFIVNLAVADLLLSATVLPFSATMEVLGFWAFGRAFCDVWAAVDVLCC
  TASILSLCTISVDRYVGVRHSLKYPAIMTERKAAAILALLWVVALVVSVGPLLGWKEPVP
  PDERFCGITEEAGYAVFSSVCSFYLPMAVIVVMYCRVYVVARSTTRSLEAGVKRERGKAS
  EVVLRIHCRGAATGADGAHGMRSAKGHTFRSSLSVRLLKFSREKKAAKTLAIVVGVFVLC
  WFPFFFVLPLGSLFPQLKPSEGVFKVIFWLGYFNSCVNPLIYPCSSREFKRAFLRLLRCQ
  CRRRRRRRPLWRVYGHHWRASTSGLRQDCAPSSGDAPPGAPLALTALPDPDPEPPGTPEM
  QAPVASRRKPPSAFREWRLLGPFRRPTTQLRAKVSSLSHKIRAGGAQRAEAACAQRSEVE
  AVSLGVPHEVAEGATCQAYELADYSNLRETDI
• Function: This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Neuroactive ligand-receptor interaction (hsa04080)
  Adrenergic sig.ling in cardiomyocytes (hsa04261)
  Vascular smooth muscle contraction (hsa04270)
  Salivary secretion (hsa04970)
• Reactome Pathway:
  G alpha (q) signalling events (R-HSA-416476)
  G alpha (12/13) signalling events (R-HSA-416482)
  Adrenoceptors (R-HSA-390696)

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
Domperidone	DMBDPY0	Approved	Alpha-1D adrenergic receptor (ADRA1D) affects the response to substance of Domperidone.	[16]
Metoclopramide	DMFA5MY	Approved	Alpha-1D adrenergic receptor (ADRA1D) increases the response of Metoclopramide.	[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	Alpha-1D adrenergic receptor (ADRA1D) increases the abundance of D-myo-inositol 1,4,5-trisphosphate.	[9]

2 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 Alpha-1D adrenergic receptor (ADRA1D).	[1]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Alpha-1D adrenergic receptor (ADRA1D).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Alpha-1D adrenergic receptor (ADRA1D).	[2]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Alpha-1D adrenergic receptor (ADRA1D).	[3]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Alpha-1D adrenergic receptor (ADRA1D).	[4]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Alpha-1D adrenergic receptor (ADRA1D).	[5]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Alpha-1D adrenergic receptor (ADRA1D).	[6]
Phenylephrine	DMZHUO5	Approved	Phenylephrine increases the activity of Alpha-1D adrenergic receptor (ADRA1D).	[7]
Epinephrine	DM3KJBC	Approved	Epinephrine increases the activity of Alpha-1D adrenergic receptor (ADRA1D).	[7]
Terbutaline	DMD4381	Approved	Terbutaline increases the expression of Alpha-1D adrenergic receptor (ADRA1D).	[6]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Alpha-1D adrenergic receptor (ADRA1D).	[11]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Alpha-1D adrenergic receptor (ADRA1D).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Norepinephrine	DMOUC09	Approved	Norepinephrine affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[8]
Quinidine	DMLPICK	Approved	Quinidine affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[9]
Phentolamine	DMXYJOB	Approved	Phentolamine affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[7]
Oxymetazoline	DM8ZXT6	Approved	Oxymetazoline affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[8]
Alfuzosin	DMZVMKF	Approved	Alfuzosin affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[10]
Methoxamine	DMF5XQH	Approved	Methoxamine affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[8]
Xylometazoline	DMKV32D	Phase 4	Xylometazoline affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[12]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[9]
BMY-7378	DMRHCEG	Terminated	BMY-7378 affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[15]
SK&F-104856	DMN91EK	Terminated	SK&F-104856 affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[10]
5-methylurapidil	DMCX9WN	Investigative	5-methylurapidil affects the binding of Alpha-1D adrenergic receptor (ADRA1D).	[8]

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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [3] Identification of transcriptional biomarkers induced by SERMS in human endometrial cells using multivariate analysis of DNA microarrays. Biomarkers. 2004 Nov-Dec;9(6):447-60.
• [4] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [5] Epigenetic regulation of human alpha1d-adrenergic receptor gene expression: a role for DNA methylation in Sp1-dependent regulation. FASEB J. 2007 Jul;21(9):1979-93. doi: 10.1096/fj.06-7118com. Epub 2007 Mar 23.
• [6] Neuroendocrine mediators up-regulate alpha1b- and alpha1d-adrenergic receptor subtypes in human monocytes. J Neuroimmunol. 1999 Mar 1;95(1-2):165-73. doi: 10.1016/s0165-5728(99)00011-9.
• [7] Carvedilol selectively inhibits oscillatory intracellular calcium changes evoked by human alpha1D- and alpha1B-adrenergic receptors. Cardiovasc Res. 2004 Sep 1;63(4):662-72. doi: 10.1016/j.cardiores.2004.05.014.
• [8] Chromatography studies on bio-affinity of nine ligands of alpha1-adrenoceptor to alpha1D subtypes overexpressed in cell membrane. Sci China C Life Sci. 2004 Aug;47(4):376-81. doi: 10.1360/03yc0109.
• [9] Effects of quinidine and verapamil on human cardiovascular alpha1-adrenoceptors. Circulation. 1998 Apr 7;97(13):1227-30. doi: 10.1161/01.cir.97.13.1227.
• [10] The alpha 1-adrenergic receptor that mediates smooth muscle contraction in human prostate has the pharmacological properties of the cloned human alpha 1c subtype. Mol Pharmacol. 1994 Apr;45(4):703-8.
• [11] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [12] Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline. Fundam Clin Pharmacol. 2010 Dec;24(6):729-39.
• [13] 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.
• [14] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [15] Heterodimers of alpha1B- and alpha1D-adrenergic receptors form a single functional entity. Mol Pharmacol. 2006 Jan;69(1):45-55. doi: 10.1124/mol.105.014985. Epub 2005 Sep 29.
• [16] Domperidone treatment for gastroparesis: demographic and pharmacogenetic characterization of clinical efficacy and side-effects. Dig Dis Sci. 2011 Jan;56(1):115-24. doi: 10.1007/s10620-010-1472-2. Epub 2010 Nov 10.
• [17] Clinical response and side effects of metoclopramide: associations with clinical, demographic, and pharmacogenetic parameters. J Clin Gastroenterol. 2012 Jul;46(6):494-503. doi: 10.1097/MCG.0b013e3182522624.