Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTR6W5O)

• DTT Name: Adrenergic receptor beta-1 (ADRB1)
• Synonyms: Beta-1 adrenoreceptor; Beta-1 adrenoceptor; Beta-1 adrenergic receptor; B1AR; ADRB1R
• Gene Name: ADRB1
• DTT Type: Successful target; [1]
• Related Disease:
  Allergic/hypersensitivity disorder [ICD-11: 4A80-4A8Z]
  Asthma [ICD-11: CA23]
  Cardiac arrhythmia [ICD-11: BC9Z]
  Central and peripheral nervous disease [ICD-11: 8A04-8E7Z]
  Circulatory system disease [ICD-11: BE2Z]
  Conduction disorder [ICD-11: BC63]
  Coronary atherosclerosis [ICD-11: BA80]
  Essential hypertension [ICD-11: BA00]
  Glaucoma [ICD-11: 9C61]
  Heart failure [ICD-11: BD10-BD1Z]
  Hypertension [ICD-11: BA00-BA04]
  Migraine [ICD-11: 8A80]
  Sepsis [ICD-11: 1G40-1G41]
  Supraventricular tachyarrhythmia [ICD-11: BC81]
  Ventricular tachyarrhythmia [ICD-11: BC71]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: ADRB1_HUMAN
• TTD ID: T44068
• Sequence:
  MGAGVLVLGASEPGNLSSAAPLPDGAATAARLLVPASPPASLLPPASESPEPLSQQWTAG
  MGLLMALIVLLIVAGNVLVIVAIAKTPRLQTLTNLFIMSLASADLVMGLLVVPFGATIVV
  WGRWEYGSFFCELWTSVDVLCVTASIETLCVIALDRYLAITSPFRYQSLLTRARARGLVC
  TVWAISALVSFLPILMHWWRAESDEARRCYNDPKCCDFVTNRAYAIASSVVSFYVPLCIM
  AFVYLRVFREAQKQVKKIDSCERRFLGGPARPPSPSPSPVPAPAPPPGPPRPAAAAATAP
  LANGRAGKRRPSRLVALREQKALKTLGIIMGVFTLCWLPFFLANVVKAFHRELVPDRLFV
  FFNWLGYANSAFNPIIYCRSPDFRKAFQRLLCCARRAARRRHATHGDRPRASGCLARPGP
  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.
• KEGG Pathway:
  Calcium signaling pathway (hsa04020)
  cGMP-PKG signaling pathway (hsa04022)
  cAMP signaling pathway (hsa04024)
  Neuroactive ligand-receptor interaction (hsa04080)
  Endocytosis (hsa04144)
  Adrenergic signaling in cardiomyocytes (hsa04261)
  Gap junction (hsa04540)
  Salivary secretion (hsa04970)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Adrenoceptors (R-HSA-390696)

Molecular Interaction Atlas (MIA) of This DTT

30 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Acebutolol	DM0TI4U	Hypertension	BA00-BA04	Approved	[2], [3]
Ajmalicine	DMPOD47	Circulatory disorder	BE2Z	Approved	[4]
Anisodamine	DMW51AX	Central and peripheral nervous disease	8A04-8E7Z	Approved	[4]
Anisodine	DMNOSWU	Central and peripheral nervous disease	8A04-8E7Z	Approved	[4]
Arbutamine	DMCY8AF	Coronary artery disease	BA80	Approved	[5]
Atenolol	DMNKG1Z	Hypertension	BA00-BA04	Approved	[2], [3]
Betaxolol	DM6EUL5	Hypertension	BA00-BA04	Approved	[6], [7]
Bisoprolol	DM3UZ95	Hypertension	BA00-BA04	Approved	[8], [9]
Bretylium	DM1FX74	Ventricular fibrillation	BC71.1	Approved	[10], [11]
Carteolol	DMFMDOB	Glaucoma/ocular hypertension	9C61	Approved	[12], [13]
Dipivefrin	DMH5W0G	Chronic open-angle glaucoma	9C61.0	Approved	[14]
Dobutamine	DMD1B8Z	Heart failure	BD10-BD13	Approved	[15], [9]
Epinephrine	DM3KJBC	Allergy	4A80-4A85	Approved	[16]
Esmolol	DM51TYR	Acute supraventricular tachycardia	BC81	Approved	[17]
Isoproterenol	DMK7MEY	Heart block	BC63	Approved	[3]
Levobetaxolol	DMSREPX	Chronic open-angle glaucoma	9C61.0	Approved	[18]
Levobunolol	DMTNFCQ	Open-angle glaucoma	9C61	Approved	[1]
Metipranolol	DMJMVKI	Open-angle glaucoma	9C61	Approved	[19]
Metoprolol	DMOJ0V6	Hypertension	BA00-BA04	Approved	[2], [20], [3]
Nadolol	DMW6GVL	High blood pressure	BA00	Approved	[21]
Nebivolol	DM7F1PA	Hypertension	BA00-BA04	Approved	[22]
Norepinephrine	DMOUC09	Sepsis	1G40-1G41	Approved	[23]
Oxprenolol	DM51OQW	Hypertension	BA00-BA04	Approved	[2]
Penbutolol	DM4ES8F	Hypertension	BA00-BA04	Approved	[24], [25]
Pindolol	DMD2NV7	Hypertension	BA00-BA04	Approved	[26]
Practolol	DMGLZ26	Cardiac arrhythmias	BC9Z	Approved	[27], [28]
Propranolol	DM79NTF	Migraine	8A80	Approved	[29]
Protokylol Hydrochloride	DMAHZKR	Asthma	CA23	Approved	[30]
Sotalol	DML60TN	Sinus rhythm disorder	BC9Y	Approved	[31]
Timolol	DM3NXRU	High blood pressure	BA00	Approved	[32], [33], [34]

6 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Bucindolol	DMV52CP	Atrial fibrillation	BC81.3	Phase 2/3	[35], [36], [37]
BRL 35135	DMLFGHX	Diabetic complication	5A2Y	Phase 2	[38]
COR-1	DMER82Z	Heart failure	BD10-BD13	Phase 2	[39]
Galnobax	DMQU4EI	Diabetic foot ulcer	BD54	Phase 1/2	[40]
L-796568	DMXKO1L	Obesity	5B81	Phase 1	[41]
YM-16151-4	DMNLY9R	Hypertension	BA00-BA04	Phase 1	[42]

4 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Alprenolol	DMYJ8Z3	Hypertension	BA00-BA04	Withdrawn from market	[43], [44]
Bethanidine	DMJMHNL	Heart arrhythmia	BC65	Withdrawn from market	[45]
Cetamolol	DMIDFLV	Angina pectoris	BA40	Terminated	[46], [39]
L-755507	DMPWBNU	N. A.	N. A.	Terminated	[47]

12 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(+/-)-nantenine	DM0L3GE	Discovery agent	N.A.	Investigative	[48]
(R,R)-(-)-fenoterol	DM3FQYS	Discovery agent	N.A.	Investigative	[49]
(R,S)-(-)-fenoterol	DMETQBI	Discovery agent	N.A.	Investigative	[49]
1-(1H-Indol-4-yloxy)-3-phenethylamino-propan-2-ol	DMSUPCD	Discovery agent	N.A.	Investigative	[50]
1-(2-allylphenoxy)-3-morpholinopropan-2-ol	DMLV0PQ	Discovery agent	N.A.	Investigative	[51]
1-(2-isopropylphenoxy)-3-morpholinopropan-2-ol	DMK209P	Discovery agent	N.A.	Investigative	[51]
4-(4-butylpiperidin-1-yl)-1-o-tolylbutan-1-one	DMM9X0G	Discovery agent	N.A.	Investigative	[52]
Carazolol	DMEKI1J	Discovery agent	N.A.	Investigative	[3]
Cebutolol	DMUKGEA	Discovery agent	N.A.	Investigative	[3]
CGP 20712A	DML79NU	Discovery agent	N.A.	Investigative	[53], [54]
Dichloroisoproterenol	DMSZ7UE	Discovery agent	N.A.	Investigative	[55]
[3H]CGP12177	DMZN1A3	Discovery agent	N.A.	Investigative	[47]

References

• [1] Binding of beta-adrenoceptor antagonists to rat and rabbit lung: special reference to levobunolol. Arzneimittelforschung. 1984;34(5):579-84.
• [2] Prediction and experimental validation of acute toxicity of beta-blockers in Ceriodaphnia dubia. Environ Toxicol Chem. 2005 Oct;24(10):2470-6.
• [3] Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. Eur J Clin Pharmacol. 1998 Feb;53(6):389-404.
• [4] Medicinal plants in therapy. Bull World Health Organ. 1985;63(6):965-81.
• [5] Characterization of the adrenergic activity of arbutamine, a novel agent for pharmacological stress testing. Cardiovasc Drugs Ther. 1996 Mar;10(1):39-47.
• [6] beta-adrenergic enhancement of brain kynurenic acid production mediated via cAMP-related protein kinase A signaling. Prog Neuropsychopharmacol Biol Psychiatry. 2009 Apr 30;33(3):519-29.
• [7] Betaxolol, a beta(1)-adrenoceptor antagonist, reduces Na(+) influx into cortical synaptosomes by direct interaction with Na(+) channels: comparison with other beta-adrenoceptor antagonists. Br J Pharmacol. 2000 Jun;130(4):759-66.
• [8] Antiarrhythmic effect of bisoprolol, a highly selective beta1-blocker, in patients with paroxysmal atrial fibrillation. Int Heart J. 2008 May;49(3):281-93.
• [9] Autoimmunity in idiopathic dilated cardiomyopathy. Characterization of antibodies against the beta 1-adrenoceptor with positive chronotropic effect. Circulation. 1994 Jun;89(6):2760-7.
• [10] Components of functional sympathetic control of heart rate in neonatal rats. Am J Physiol. 1985 May;248(5 Pt 2):R601-10.
• [11] Dissociation of autonomic controls of heart rate in weaning-aged borderline hypertensive rats by perinatal NaCl. J Auton Nerv Syst. 1990 Mar;29(3):219-26.
• [12] Partial agonistic effects of carteolol on atypical beta-adrenoceptors in the guinea pig gastric fundus. Jpn J Pharmacol. 2000 Nov;84(3):287-92.
• [13] Effects of prolonged treatment with beta-adrenoceptor antagonist, carteolol on systemic and regional hemodynamics in stroke-prone spontaneously hypertensive rats. J Pharmacobiodyn. 1991 Feb;14(2):94-100.
• [14] Contractile response of the isolated trabecular meshwork and ciliary muscle to cholinergic and adrenergic agents. Ger J Ophthalmol. 1996 May;5(3):146-53.
• [15] Beta-adrenoceptor alterations coupled with secretory response and experimental periodontitis in rat submandibular glands. Arch Oral Biol. 2008 Jun;53(6):509-16.
• [16] Adrenergic activation of electrogenic K+ secretion in guinea pig distal colonic epithelium: involvement of beta1- and beta2-adrenergic receptors. Am J Physiol Gastrointest Liver Physiol. 2009 Aug;297(2):G269-77.
• [17] Beta-1 selective adrenergic antagonist landiolol and esmolol can be safely used in patients with airway hyperreactivity. Heart Lung. 2009 Jan-Feb;38(1):48-55.
• [18] Binding affinities of ocular hypotensive beta-blockers levobetaxolol, levobunolol, and timolol at endogenous guinea pig beta-adrenoceptors. J Ocul Pharmacol Ther. 2004 Apr;20(2):93-9.
• [19] Invited review: Neuroprotective properties of certain beta-adrenoceptor antagonists used for the treatment of glaucoma. J Ocul Pharmacol Ther. 2005 Jun;21(3):175-81.
• [20] Knockouts model the 100 best-selling drugs--will they model the next 100 Nat Rev Drug Discov. 2003 Jan;2(1):38-51.
• [21] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [22] Nitric oxide mechanisms of nebivolol. Ther Adv Cardiovasc Dis. 2009 Aug;3(4):317-27.
• [23] Impact of exogenous beta-adrenergic receptor stimulation on hepatosplanchnic oxygen kinetics and metabolic activity in septic shock. Crit Care Med. 1999 Feb;27(2):325-31.
• [24] beta-Adrenergic receptor blockers--a group of chiral drugs: different effects of each enantiomer. Ceska Slov Farm. 2002 May;51(3):121-8.
• [25] Decrease in penbutolol central response as a cause of changes in its serum protein binding. J Pharm Pharmacol. 1990 Mar;42(3):164-6.
• [26] Are we misunderstanding beta-blockers. Int J Cardiol. 2007 Aug 9;120(1):10-27.
• [27] Prostaglandin E2 synthesis elicited by adrenergic stimuli in guinea pig trachea is mediated primarily via activation of beta 2 adrenergic receptors. Prostaglandins. 1992 Nov;44(5):399-412.
• [28] TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5.
• [29] Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
• [30] N-Aralkyl substitution increases the affinity of adrenergic drugs for the alpha-adrenoceptor in rat liver.
• [31] beta(2)-adrenoceptors are critical for antidepressant treatment of neuropathic pain. Ann Neurol. 2009 Feb;65(2):218-25.
• [32] Topical dorzolamide 2%/timolol 0.5% ophthalmic solution: a review of its use in the treatment of glaucoma and ocular hypertension. Drugs Aging. 2006;23(12):977-95.
• [33] Blockade of beta-adrenergic receptors prevents amphetamine-induced behavioural sensitization in rats: a putative role of the bed nucleus of the str... Int J Neuropsychopharmacol. 2005 Dec;8(4):569-81.
• [34] A prospective study of the effects of prolonged timolol therapy on alpha- and beta-adrenoceptor and angiotensin II receptor mediated responses in normal subjects. Br J Clin Pharmacol. 1997 Mar;43(3):301-8.
• [35] Bucindolol has serotonin and alpha-adrenoceptor blocking properties. J Cardiovasc Pharmacol. 1985;7 Suppl 7:S67-9.
• [36] Bucindolol, a nonselective beta 1- and beta 2-adrenergic receptor antagonist, decreases beta-adrenergic receptor density in cultured embryonic chic... J Cardiovasc Pharmacol. 2001 Jun;37(6):678-91.
• [37] Bucindolol: new hopes from reviewing past data.Drugs Today (Barc).2011 May;47(5):347-51.
• [38] Clinical pharmacology of beta 3-adrenoceptors. Br J Clin Pharmacol. 1996 Sep;42(3):291-300.
• [39] Administration of the cyclic peptide COR-1 in humans (phase I study): ex vivo measurements of anti-beta1-adrenergic receptor antibody neutralization and of immune parameters. Eur J Heart Fail. 2012 Nov;14(11):1230-9.
• [40] Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA)
• [41] Heterocyclic acetamide and benzamide derivatives as potent and selective beta3-adrenergic receptor agonists with improved rodent pharmacokinetic pr... Bioorg Med Chem Lett. 2010 Mar 15;20(6):1895-9.
• [42] Antianginal effects of YM-16151-4 in various experimental angina models. J Cardiovasc Pharmacol. 1993 May;21(5):701-8.
• [43] Beta-blockers alprenolol and carvedilol stimulate beta-arrestin-mediated EGFR transactivation. Proc Natl Acad Sci U S A. 2008 Sep 23;105(38):14555-60.
• [44] Inverse agonist activities of beta-adrenoceptor antagonists in rat myocardium. Br J Pharmacol. 1999 Jun;127(4):895-902.
• [45] Withdrawal syndromes and the cessation of antihypertensive therapy. Arch Intern Med. 1981 Aug;141(9):1125-7.
• [46] Comparison of the beta-adrenoceptor affinity and selectivity of cetamolol, atenolol, betaxolol, and ICI-118,551. J Cardiovasc Pharmacol. 1988 Aug;12(2):208-17.
• [47] (4-Piperidin-1-yl)phenyl amides: potent and selective human beta(3) agonists. J Med Chem. 2001 Apr 26;44(9):1456-66.
• [48] Synthetic studies and pharmacological evaluations on the MDMA ('Ecstasy') antagonist nantenine. Bioorg Med Chem Lett. 2010 Jan 15;20(2):628-31.
• [49] Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor. J Med Chem. 2007 Jun 14;50(12):2903-15.
• [50] Synthesis and beta-adrenergic receptor blocking potency of 1-(substituted amino)-3-(4-indolyloxy)propan-2-ols. J Med Chem. 1986 Aug;29(8):1524-7.
• [51] A vHTS approach for the identification of beta-adrenoceptor ligands. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3399-404.
• [52] Discovery of N-{1-[3-(3-oxo-2,3-dihydrobenzo[1,4]oxazin-4-yl)propyl]piperidin-4-yl}-2-phenylacetamide (Lu AE51090): an allosteric muscarinic M1 rec... J Med Chem. 2010 Sep 9;53(17):6386-97.
• [53] Distribution of beta 1- and beta 2-adrenoceptor subtypes in various mouse tissues. Neurosci Lett. 1993 Sep 17;160(1):96-100.
• [54] Uptake of radioligands by rat heart and lung in vivo: CGP 12177 does and CGP 26505 does not reflect binding to beta-adrenoceptors. Eur J Pharmacol. 1992 Nov 3;222(1):107-12.
• [55] The [(methyloxy)imino]methyl moiety as a bioisoster of aryl. A novel class of completely aliphatic beta-adrenergic receptor antagonists. J Med Chem. 1994 May 13;37(10):1518-25.