Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TT2CJVK)

• DTT Name: Adrenergic receptor beta-2 (ADRB2)
• Synonyms: Beta-2 adrenoreceptor; Beta-2 adrenoceptor; Beta-2 adrenergic receptor; B2AR; ADRB2R
• Gene Name: ADRB2
• DTT Type: Successful target; [1]
• BioChemical Class: GPCR rhodopsin
• UniProt ID: ADRB2_HUMAN
• TTD ID: T52522
• Sequence:
  MGQPGNGSAFLLAPNGSHAPDHDVTQERDEVWVVGMGIVMSLIVLAIVFGNVLVITAIAK
  FERLQTVTNYFITSLACADLVMGLAVVPFGAAHILMKMWTFGNFWCEFWTSIDVLCVTAS
  IETLCVIAVDRYFAITSPFKYQSLLTKNKARVIILMVWIVSGLTSFLPIQMHWYRATHQE
  AINCYANETCCDFFTNQAYAIASSIVSFYVPLVIMVFVYSRVFQEAKRQLQKIDKSEGRF
  HVQNLSQVEQDGRTGHGLRRSSKFCLKEHKALKTLGIIMGTFTLCWLPFFIVNIVHVIQD
  NLIRKEVYILLNWIGYVNSGFNPLIYCRSPDFRIAFQELLCLRRSSLKAYGNGYSSNGNT
  GEQSGYHVEQEKENKLLCEDLPGTEDFVGHQGTVPSDNIDSQGRNCSTNDSLL
• Function: The beta-2-adrenergic receptor binds epinephrine with an approximately 30-fold greater affinity than it does norepinephrine. Beta-adrenergic receptors mediate the catecholamine-induced activation of adenylate cyclase through the action of G proteins.
• 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)
  Salivary secretion (hsa04970)
• Reactome Pathway:
  G alpha (s) signalling events (R-HSA-418555)
  Adrenoceptors (R-HSA-390696)

Molecular Interaction Atlas (MIA) of This DTT

19 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Arformoterol	DMYM974	Chronic obstructive pulmonary disease	CA22	Approved	[2]
Bambuterol	DMKLSHF	Asthma	CA23	Approved	[3]
Clenbuterol	DMCKYZ5	Chronic breathing disorder	7A4Z	Approved	[4]
Fenoterol	DMIP3ZV	Asthma	CA23	Approved	[5]
Formoterol	DMSOURV	Allergic asthma	CA23.0	Approved	[6]
GW642444	DMV4KOA	Asthma	CA23	Approved	[7]
Indacaterol	DMQJHR7	Chronic obstructive pulmonary disease	CA22	Approved	[8]
Isoetharine	DMITSEH	Asthma	CA23	Approved	[9]
Isoproterenol	DMK7MEY	Atrioventricular block		Approved	[10]
Levalbuterol	DM5YBO1	Asthma	CA23	Approved	[11]
Metaproterenol Sulfate	DMTQS9A	Asthma	CA23	Approved	[12]
Olodaterol	DM62B78	Chronic obstructive pulmonary disease	CA22	Approved	[13]
Pirbuterol	DMI5678	Asthma	CA23	Approved	[14]
Procaterol	DM1M0Q4	Asthma	CA23	Approved	[15]
Ritodrine	DM4V6RL	Premature labour	JB00	Approved	[9]
Salbutamol	DMN9CWF	Acute asthma	CA23	Approved	[16]
Salmeterol	DMIEU69	Allergic asthma	CA23.0	Approved	[17]
Terbutaline	DMD4381	Asthma	CA23	Approved	[1]
Vilanterol	DMF5EK1	Chronic obstructive pulmonary disease	CA22	Approved	[18]

17 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
GSK642444	DMUVZAO	Chronic obstructive pulmonary disease	CA22	Phase 3	[19]
ICI 118,551	DM3OU54	Gastric adenocarcinoma	2B72	Phase 3	[20]
PT005	DMTSN8L	Chronic obstructive pulmonary disease	CA22	Phase 3	[21]
QVA-149	DMSFX75	Chronic obstructive pulmonary disease	CA22	Phase 3	[8]
BUCINDOLOL	DMV52CP	Atrial fibrillation	BC81.3	Phase 2/3	[22]
APD-209	DMNQ7DV	Cachexia	MG20	Phase 2	[23]
AZD-2115	DMGQSVX	Chronic obstructive pulmonary disease	CA22	Phase 2	[24]
AZD-3199	DME8Z5M	Asthma	CA23	Phase 2	[25]
Carmoterol	DMN6TKI	Chronic obstructive pulmonary disease	CA22	Phase 2	[8]
GSK961081	DM6DKF9	Chronic obstructive pulmonary disease	CA22	Phase 2	[26]
LAS 100977	DMPRZX4	Chronic obstructive pulmonary disease	CA22	Phase 2	[27]
MN-221	DMBX2RE	Aging skin	EE40	Phase 2	[28]
R-salbutamol sulphate	DMGLCVU	Skin infection	1F28-1G0Z	Phase 2	[29]
TA-2005	DMMWPSQ	Chronic obstructive pulmonary disease	CA22	Phase 2	[30]
THRX-198321	DM1BYNF	Chronic obstructive pulmonary disease	CA22	Phase 2	[31]
KUL-7211	DMKFVX5	Neurogenic bladder dysfunction	GC01.4	Phase 1	[32]
L-796568	DMXKO1L	Obesity	5B81	Phase 1	[33]

12 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Meluadrine	DMEQDHP	Premature ejaculation	HA03.0Z	Discontinued in Preregistration	[34]
Broxaterol	DMRA6H5	Asthma	CA23	Discontinued in Phase 3	[35]
Sibenadet	DMYQT2V	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 3	[36]
GSK-159797	DMTZBXQ	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 2	[30]
GSK159802	DM8J2AV	Asthma	CA23	Discontinued in Phase 2	[7]
Milveterol	DMF1IH5	Asthma	CA23	Discontinued in Phase 2	[7]
PF-610355	DM6XEQA	Chronic obstructive pulmonary disease	CA22	Discontinued in Phase 2	[37]
Picumeterol	DMA13WI	Asthma	CA23	Discontinued in Phase 2	[38]
AR-C-89855	DM9HZ8D	Chronic obstructive pulmonary disease	CA22	Terminated	[39]
DPI-201-106	DM1AQVE	Cardiovascular disease	BA00-BE2Z	Terminated	[40]
L-755507	DMPWBNU	N. A.	N. A.	Terminated	[41]
RP-58802B	DMQZ2JA	Asthma	CA23	Terminated	[42]

11 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
(R,R)-(-)-fenoterol	DM3FQYS	Discovery agent	N.A.	Investigative	[43]
(R,S)-(-)-fenoterol	DMETQBI	Discovery agent	N.A.	Investigative	[43]
(S,R)-(+)-fenoterol	DMA30RW	Discovery agent	N.A.	Investigative	[43]
1-(2-allylphenoxy)-3-morpholinopropan-2-ol	DMLV0PQ	Discovery agent	N.A.	Investigative	[44]
1-(2-isopropylphenoxy)-3-morpholinopropan-2-ol	DMK209P	Discovery agent	N.A.	Investigative	[44]
2-fluoronorepinehprine	DMX34TL	Discovery agent	N.A.	Investigative	[45]
Butoxamine	DM7XN2J	Discovery agent	N.A.	Investigative	[46]
D 2343	DM1E5C4	Discovery agent	N.A.	Investigative	[47]
Dichloroisoproterenol	DMSZ7UE	Discovery agent	N.A.	Investigative	[48]
GNF-PF-1694	DM4JZ9A	Discovery agent	N.A.	Investigative	[40]
[3H]CGP12177	DMZN1A3	Discovery agent	N.A.	Investigative	[41]

Molecular Expression Atlas (MEA) of This DTT

Disease Name	ICD 11	Studied Tissue	p-value	Fold-Change	Z-score
Chronic obstructive pulmonary disease	CA23	Lung tissue	4.88E-01	-0.05	-0.12
Chronic obstructive pulmonary disease	CA23	Small airway epithelium	7.10E-01	0.06	0.09
Asthma	CA23	Nasal and bronchial airway	3.52E-02	0.25	0.34

References

• [1] Evaluation of a new oral beta2-adrenoceptor stimulant bronchodilator, terbutaline. Pharmacology. 1975;13(3):201-11.
• [2] Arformoterol tartrate in the treatment of bronchoconstriction in patients with chronic obstructive pulmonary disease. Drugs Today (Barc). 2009 Jan;45(1):3-9.
• [3] Enantiomeric separation of beta2-agonists on macrocyclic antibiotic chiral stationary phases in high performance liquid chromatography. Pharmazie. 2007 Nov;62(11):836-40.
• [4] Postischemic brain injury is attenuated in mice lacking the beta2-adrenergic receptor. Anesth Analg. 2009 Jan;108(1):280-7.
• [5] Functional alpha1- and beta2-adrenergic receptors in human osteoblasts. J Cell Physiol. 2009 Jul;220(1):267-75.
• [6] Long-acting beta2-agonists for chronic obstructive pulmonary disease patients with poorly reversible airflow limitation. Cochrane Database Syst Rev. 2002;(3):CD001104.
• [7] Clinical pipeline report, company report or official report of GlaxoSmithKline (2009).
• [8] Emerging drugs in chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2009 Mar;14(1):181-94.
• [9] Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services.
• [10] Current therapeutic uses and potential of beta-adrenoceptor agonists and antagonists. Eur J Clin Pharmacol. 1998 Feb;53(6):389-404.
• [11] Beta-blockers in the treatment of hypertension: are there clinically relevant differences Postgrad Med. 2009 May;121(3):90-8.
• [12] Male--female differences in the impact of beta-adrenoceptor stimulation on resistance to experimental metastasis: exploring the effects of age and ... J Neuroimmunol. 2008 Jan;193(1-2):113-9.
• [13] 2014 FDA drug approvals. Nat Rev Drug Discov. 2015 Feb;14(2):77-81.
• [14] Inhaled beta agonists. Respir Care. 2007 Jul;52(7):820-32.
• [15] Inhalation and incubation with procaterol increases diaphragm muscle contractility in mice. Allergol Int. 2007 Sep;56(3):285-91.
• [16] Potential of beta2-adrenoceptor agonists as add-on therapy for multiple sclerosis: focus on salbutamol (albuterol). CNS Drugs. 2002;16(1):1-8.
• [17] Pharmacogenetic tests in asthma therapy. Clin Lab Med. 2008 Dec;28(4):645-65.
• [18] URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7353).
• [19] Radium 223 dichloride for prostate cancer treatment. Drug Des Devel Ther. 2017 Sep 6;11:2643-2651.
• [20] Selective beta 2-adrenoceptor antagonists: derivatives of ICI 118,551 and a binary aryloxypropanolamine. J Pharm Pharmacol. 1988 Nov;40(11):803-5.
• [21] Clinical pipeline report, company report or official report of Pearl Therapeutics.
• [22] Bucindolol has serotonin and alpha-adrenoceptor blocking properties. J Cardiovasc Pharmacol. 1985;7 Suppl 7:S67-9.
• [23] Drugs in development for treatment of patients with cancer-related anorexia and cachexia syndrome. Retraction in: Drug Des Devel Ther. 2013; 7: 1385.
• [24] Evaluation of WO-2012085582 and WO-2012085583 two identified MABAs: backups to AZD-2115. Expert Opin Ther Pat. 2012 Nov;22(11):1377-83.
• [25] Clinical pharmacokinetics of AZD3199, an inhaled ultra-long-acting beta2-adrenoreceptor agonist (uLABA). Drug Des Devel Ther. 2015; 9: 753-762.
• [26] Pharmacologic characterization of GSK-961081 (TD-5959), a first-in-class inhaled bifunctional bronchodilator possessing muscarinic receptor antagonist and 2-adrenoceptor agonist properties.J Pharmacol Exp Ther.2014 Oct;351(1):190-9.
• [27] Pharmacological characterization of abediterol, a novel inhaled beta(2)-adrenoceptor agonist with long duration of action and a favorable safety profile in preclinical models. J Pharmacol Exp Ther. 2012 Aug;342(2):497-509.
• [28] Investigation of beta(2)-adrenoceptor subtype selectivity and organ specificity for bedoradrine (KUR-1246), a novel tocolytic beta-adrenergic receptor stimulant. J Obstet Gynaecol Res. 2009 Jun;35(3):405-13.
• [29] Pharmacokinetics and extrapulmonary beta 2 adrenoceptor activity of nebulised racemic salbutamol and its R and S isomers in healthy volunteers. Thorax. 1997 Oct;52(10):849-52.
• [30] Emerging drugs for the treatment of chronic obstructive pulmonary disease. Expert Opin Emerg Drugs. 2006 May;11(2):275-91.
• [31] THRX-198321 is a bifunctional muscarinic receptor antagonist and beta2-adrenoceptor agonist (MABA) that binds in a bimodal and multivalent manner. Mol Pharmacol. 2011 Mar;79(3):389-99.
• [32] The potency of KUL-7211, a selective ureteral relaxant, in isolated canine ureter: comparison with various spasmolytics.Urol Res.2005 Dec;33(6):409-14.
• [33] 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.
• [34] Effects of meluadrine tartrate and ritodrine hydrochloride on oxytocin-induced uterine contraction, uterine arterial blood flow and maternal cardiovascular function in pregnant goats. Jpn J Pharmacol. 2002 Oct;90(2):107-13.
• [35] Broxaterol, a new beta 2-adrenoceptor agonist compared to salbutamol in asthmatics, oral and inhalation treatment. Respiration. 1989;55 Suppl 2:15-9.
• [36] The role of the novel D2/beta2-agonist, Viozan (sibenadet HCl), in the treatment of symptoms of chronic obstructive pulmonary disease: results of a... Respir Med. 2003 Jan;97 Suppl A:S23-33.
• [37] Inhalation by design: novel ultra-long-acting beta(2)-adrenoreceptor agonists for inhaled once-daily treatment of asthma and chronic obstructive pulmonary disease that utilize a sulfonamide agonist headgroup. J Med Chem. 2010 Sep 23;53(18):6640-52.
• [38] Picumeterol: dissociation of improvement in lung function and reduction of airways hyperresponsiveness in asthmatics. Br J Clin Pharmacol. 1997 Feb;43(2):169-76.
• [39] Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013263)
• [40] Use of the X-ray structure of the beta2-adrenergic receptor for drug discovery. Part 2: Identification of active compounds. Bioorg Med Chem Lett. 2008 Oct 15;18(20):5391-5.
• [41] (4-Piperidin-1-yl)phenyl amides: potent and selective human beta(3) agonists. J Med Chem. 2001 Apr 26;44(9):1456-66.
• [42] RP 58802B, a long-acting beta 2-adrenoceptor agonist: assessment of antiasthma activity in the guinea-pig in vivo. Pulm Pharmacol. 1992 Sep;5(3):203-12.
• [43] 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.
• [44] A vHTS approach for the identification of beta-adrenoceptor ligands. Bioorg Med Chem Lett. 2010 Jun 1;20(11):3399-404.
• [45] Structural basis of the selectivity of the beta(2)-adrenergic receptor for fluorinated catecholamines. Bioorg Med Chem. 2009 Dec 1;17(23):7987-92.
• [46] Partial agonistic effects of carteolol on atypical beta-adrenoceptors in the guinea pig gastric fundus. Jpn J Pharmacol. 2000 Nov;84(3):287-92.
• [47] A new beta 2-adrenoceptor agonist--D 2343--with long duration. Inhalation comparison with terbutaline in asthmatics. Allergy. 1984 Aug;39(6):485-9.
• [48] 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.