Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUIWCL5)

• DOT Name: Alpha-1A adrenergic receptor (ADRA1A)
• Synonyms: Alpha-1A adrenoreceptor; Alpha-1A adrenoceptor; Alpha-1C adrenergic receptor; Alpha-adrenergic receptor 1c
• Gene Name: ADRA1A
• UniProt ID: ADA1A_HUMAN
• PDB ID: 7YM8; 7YMH; 7YMJ; 8THK; 8THL
• Pfam ID: PF00001
• Sequence:
  MVFLSGNASDSSNCTQPPAPVNISKAILLGVILGGLILFGVLGNILVILSVACHRHLHSV
  THYYIVNLAVADLLLTSTVLPFSAIFEVLGYWAFGRVFCNIWAAVDVLCCTASIMGLCII
  SIDRYIGVSYPLRYPTIVTQRRGLMALLCVWALSLVISIGPLFGWRQPAPEDETICQINE
  EPGYVLFSALGSFYLPLAIILVMYCRVYVVAKRESRGLKSGLKTDKSDSEQVTLRIHRKN
  APAGGSGMASAKTKTHFSVRLLKFSREKKAAKTLGIVVGCFVLCWLPFFLVMPIGSFFPD
  FKPSETVFKIVFWLGYLNSCINPIIYPCSSQEFKKAFQNVLRIQCLCRKQSSKHALGYTL
  HPPSQAVEGQHKDMVRIPVGSRETFYRISKTDGVCEWKFFSSMPRGSARITVSKDQSSCT
  TARVRSKSFLQVCCCVGPSTPSLDKNHQVPTIKVHTISLSENGEEV
• Function: This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) proteins. Nuclear ADRA1A-ADRA1B heterooligomers regulate phenylephrine(PE)-stimulated ERK signaling in cardiac myocytes.
• Tissue Specificity: Expressed in heart, brain, liver and prostate, but not in kidney, lung, adrenal, aorta and pituitary. Within the prostate, expressed in the apex, base, periurethral and lateral lobe. Isoform 4 is the most abundant isoform expressed in the prostate with high levels also detected in liver and heart.
• KEGG Pathway:
  Calcium sig.ling pathway (hsa04020)
  cGMP-PKG sig.ling pathway (hsa04022)
  Neuroactive ligand-receptor interaction (hsa04080)
  AMPK sig.ling pathway (hsa04152)
  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 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Gabapentin	DM6T924	Approved	Alpha-1A adrenergic receptor (ADRA1A) increases the Sleep disturbances (incl subtypes) ADR of Gabapentin.	[14]

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-1A adrenergic receptor (ADRA1A) increases the abundance of D-myo-inositol 1,4,5-trisphosphate.	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Alpha-1A adrenergic receptor (ADRA1A).	[1]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Alpha-1A adrenergic receptor (ADRA1A).	[2]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Alpha-1A adrenergic receptor (ADRA1A).	[3]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Alpha-1A adrenergic receptor (ADRA1A).	[4]
Phenylephrine	DMZHUO5	Approved	Phenylephrine increases the activity of Alpha-1A adrenergic receptor (ADRA1A).	[5]
Epinephrine	DM3KJBC	Approved	Epinephrine increases the activity of Alpha-1A adrenergic receptor (ADRA1A).	[5]
5-methylurapidil	DMCX9WN	Investigative	5-methylurapidil decreases the activity of Alpha-1A adrenergic receptor (ADRA1A).	[13]
A61603	DM7W2ME	Investigative	A61603 increases the activity of Alpha-1A adrenergic receptor (ADRA1A).	[13]

13 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-1A adrenergic receptor (ADRA1A).	[6]
Quinidine	DMLPICK	Approved	Quinidine affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[7]
Phentolamine	DMXYJOB	Approved	Phentolamine affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[5]
Oxymetazoline	DM8ZXT6	Approved	Oxymetazoline affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[8]
Alfuzosin	DMZVMKF	Approved	Alfuzosin affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[8]
Tamsulosin	DM5QF9V	Approved	Tamsulosin affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[8]
Silodosin	DMJSBT6	Approved	Silodosin affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[5]
Xylometazoline	DMKV32D	Phase 4	Xylometazoline affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[9]
Verapamil	DMA7PEW	Phase 2/3 Trial	Verapamil affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[7]
Indoramin	DMNSJFD	Withdrawn from market	Indoramin affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[11]
BMY-7378	DMRHCEG	Terminated	BMY-7378 affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[12]
WB-4101	DMQU8B1	Terminated	WB-4101 affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[6]
Niguldipine	DMSPWMF	Terminated	Niguldipine affects the binding of Alpha-1A adrenergic receptor (ADRA1A).	[6]

1 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 decreases the methylation of Alpha-1A adrenergic receptor (ADRA1A).	[10]

References

• [1] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [2] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [3] 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.
• [4] Adipogenic Effects and Gene Expression Profiling of Firemaster? 550 Components in Human Primary Preadipocytes. Environ Health Perspect. 2017 Sep 14;125(9):097013. doi: 10.1289/EHP1318.
• [5] 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.
• [6] 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.
• [7] 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.
• [8] Cell membrane chromatography competitive binding analysis for characterization of 1A adrenoreceptor binding interactions. Anal Bioanal Chem. 2011 Jul;400(10):3625-33. doi: 10.1007/s00216-011-5026-z. Epub 2011 May 5.
• [9] Alpha-adrenoceptor agonistic activity of oxymetazoline and xylometazoline. Fundam Clin Pharmacol. 2010 Dec;24(6):729-39.
• [10] 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.
• [11] Use of recombinant alpha 1-adrenoceptors to characterize subtype selectivity of drugs for the treatment of prostatic hypertrophy. Eur J Pharmacol. 1995 Jan 16;288(2):201-7. doi: 10.1016/0922-4106(95)90195-7.
• [12] 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.
• [13] Functional alpha(1)-adrenoceptor subtypes in human submandibular glands. J Dent Res. 2006 Mar;85(3):251-6. doi: 10.1177/154405910608500309.
• [14] 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.