Details of the Drug Combination

General Information of Drug Combination (ID: DC26UOZ)

• Drug Combination Name: Dobutamine + Norepinephrine
• Indication: Optimal Tissue Perfusion; Status: Phase 1 [1]
• Component Drugs:
  Dobutamine (DMD1B8Z): Small molecular drug
  Norepinephrine (DMOUC09): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Dobutamine

Disease Entry	ICD 11	Status	REF
Heart failure	BD10-BD13	Approved	[2]

Dobutamine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Agonist	[6]

Dobutamine Interacts with 1 DME Molecule(s)

DME Name	DME ID	UniProt ID	Mode of Action	REF
Catechol O-methyltransferase (COMT)	DEV3T4A	COMT_HUMAN	Metabolism	[7]

Dobutamine Interacts with 20 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Increases Methylation	[8]
Beta-1 adrenergic receptor (ADRB1)	OTQBWN4U	ADRB1_HUMAN	Affects Response To Substance	[9]
Bile salt export pump (ABCB11)	OTRU7THO	ABCBB_HUMAN	Decreases Activity	[10]
Renin (REN)	OT52GZR2	RENI_HUMAN	Increases Expression	[11]
Interleukin-1 beta (IL1B)	OT0DWXXB	IL1B_HUMAN	Decreases Expression	[12]
Interleukin-6 (IL6)	OTUOSCCU	IL6_HUMAN	Increases Expression	[13]
Interleukin-8 (CXCL8)	OTS7T5VH	IL8_HUMAN	Increases Expression	[12]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[13]
Prostaglandin G/H synthase 2 (PTGS2)	OT75U9M4	PGH2_HUMAN	Decreases Expression	[12]
Leptin (LEP)	OT5Q7ODW	LEP_HUMAN	Decreases Secretion	[14]
Tumor necrosis factor-inducible gene 6 protein (TNFAIP6)	OT1SLUZH	TSG6_HUMAN	Decreases Expression	[12]
Potassium voltage-gated channel subfamily H member 2 (KCNH2)	OTZX881H	KCNH2_HUMAN	Decreases Activity	[15]
Bile acid receptor (NR1H4)	OTWZLPTB	NR1H4_HUMAN	Increases Activity	[16]
Fibroblast growth factor 2 (FGF2)	OT7YUJ9F	FGF2_HUMAN	Affects Response To Substance	[5]
RAC-alpha serine/threonine-protein kinase (AKT1)	OT8H2YY7	AKT1_HUMAN	Affects Response To Substance	[17]
Kallikrein-1 (KLK1)	OTFGP3UR	KLK1_HUMAN	Affects Response To Substance	[18]
Nitric oxide synthase, inducible (NOS2)	OTKKIOJ1	NOS2_HUMAN	Affects Response To Substance	[19]
Neuroendocrine secretory protein 55 (GNAS)	OTMH8BKJ	GNAS3_HUMAN	Increases Response To Substance	[20]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Response To Substance	[21]
Cardiac phospholamban (PLN)	OTT3RRJN	PPLA_HUMAN	Affects Response To Substance	[22]

Indication(s) of Norepinephrine

Disease Entry	ICD 11	Status	REF
Alopecia	ED70	Approved	[3]
Bronchiectasis	CA24	Approved	[3]
Bronchitis	CA20	Approved	[3]
Chronic fatigue syndrome	8E49	Approved	[3]
Depression	6A70-6A7Z	Approved	[3]
Psychosexual disorder	N.A.	Approved	[3]
Pulmonary emphysema	CA21.Z	Approved	[3]
Pure autonomic failure	N.A.	Approved	[3]
Radiodermatitis	N.A.	Approved	[3]
Sepsis	1G40-1G41	Approved	[4]
Severe asthma	CA23	Approved	[3]
Asthma	CA23	Investigative	[3]

Norepinephrine Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Adrenergic receptor beta-1 (ADRB1)	TTR6W5O	ADRB1_HUMAN	Stimulator	[24]

Norepinephrine Interacts with 7 DTP Molecule(s)

DTP Name	DTP ID	UniProt ID	Mode of Action	REF
Organic cation transporter 2 (SLC22A2)	DT9IDPW	S22A2_HUMAN	Substrate	[25]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[25]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[26]
Vesicular amine transporter 2 (SLC18A2)	DTT7VPB	VMAT2_HUMAN	Substrate	[27]
Vesicular amine transporter 1 (SLC18A1)	DTM953D	VMAT1_HUMAN	Substrate	[27]
Sodium-dependent noradrenaline transporter (SLC6A2)	DT9JBVI	SC6A2_HUMAN	Substrate	[28]
Sodium- and chloride-dependent glycine transporter 2 (SLC6A5)	DTE8R17	SC6A5_HUMAN	Substrate	[29]

Norepinephrine Interacts with 30 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Synaptic vesicular amine transporter (SLC18A2)	OTUOMMM6	VMAT2_HUMAN	Decreases Activity	[30]
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[31]
Sodium-dependent noradrenaline transporter (SLC6A2)	OTMHQJMP	SC6A2_HUMAN	Decreases Uptake	[32]
Protein phosphatase 1 regulatory subunit 12A (PPP1R12A)	OT4AVU95	MYPT1_HUMAN	Increases Phosphorylation	[33]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[34]
Protein S100-B (S100B)	OTHHDS33	S100B_HUMAN	Increases Expression	[35]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[36]
Intercellular adhesion molecule 1 (ICAM1)	OTTOIX77	ICAM1_HUMAN	Increases Expression	[34]
Myosin light chain 1/3, skeletal muscle isoform (MYL1)	OTDUYR4U	MYL1_HUMAN	Increases Phosphorylation	[33]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[36]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Binding	[37]
72 kDa type IV collagenase (MMP2)	OT5NIWA2	MMP2_HUMAN	Increases Expression	[37]
Heme oxygenase 1 (HMOX1)	OTC1W6UX	HMOX1_HUMAN	Increases Expression	[37]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Increases Secretion	[38]
Tissue factor (F3)	OT3MSU3B	TF_HUMAN	Increases Expression	[34]
Matrix metalloproteinase-9 (MMP9)	OTB2QDAV	MMP9_HUMAN	Increases Expression	[37]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Affects Localization	[34]
Cannabinoid receptor 1 (CNR1)	OTEALO6G	CNR1_HUMAN	Affects Expression	[39]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Affects Binding	[40]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Affects Binding	[41]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[34]
Proto-oncogene c-Rel (REL)	OTTCKMAC	REL_HUMAN	Affects Localization	[34]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Increases Uptake	[42]
Pro-neuropeptide Y (NPY)	OT4ICV3P	NPY_HUMAN	Affects Response To Substance	[43]
Amine oxidase A (MAOA)	OT8NIWMQ	AOFA_HUMAN	Increases Metabolism	[44]
Sulfotransferase 1A3 (SULT1A4)	OTHJ8WWV	ST1A3_HUMAN	Increases Sulfation	[45]
Catechol O-methyltransferase (COMT)	OTPWKTQG	COMT_HUMAN	Increases Methylation	[8]
Neuron-specific vesicular protein calcyon (CALY)	OTQ7EMPU	CALY_HUMAN	Increases Secretion	[46]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Abundance	[47]
Equilibrative nucleoside transporter 4 (SLC29A4)	OTWTZXMX	S29A4_HUMAN	Increases Uptake	[31]

References

• [1] ClinicalTrials.gov (NCT03288051) Effects of Intraoperative, Goal-directed Crystalloid vs. Colloid Fluid Resuscitation on Free Flaps
• [2] 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: 535).
• [3] Norepinephrine FDA Label
• [4] 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: 505).
• [5] Gene therapy in cardiac surgery: intramyocardial injection of naked plasmid DNA for chronic myocardial ischemia. Eur J Cardiothorac Surg. 2003 Nov;24(5):785-93. doi: 10.1016/s1010-7940(03)00455-x.
• [6] Beta-adrenoceptor alterations coupled with secretory response and experimental periodontitis in rat submandibular glands. Arch Oral Biol. 2008 Jun;53(6):509-16.
• [7] Catechol-O-methyltransferase: substrate-specificity and stereoselectivity for beta-adrenoceptor agents. Xenobiotica. 1986 Jan;16(1):47-52.
• [8] Molecular mechanisms controlling the rate and specificity of catechol O-methylation by human soluble catechol O-methyltransferase. Mol Pharmacol. 2001 Feb;59(2):393-402. doi: 10.1124/mol.59.2.393.
• [9] 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.
• [10] Evaluating the Role of Multidrug Resistance Protein 3 (MDR3) Inhibition in Predicting Drug-Induced Liver Injury Using 125 Pharmaceuticals. Chem Res Toxicol. 2017 May 15;30(5):1219-1229. doi: 10.1021/acs.chemrestox.7b00048. Epub 2017 May 4.
• [11] Beta-adrenoceptor activation-induced placental prorenin secretion is mediated by increased renin messenger RNA and protein synthesis. Mol Pharmacol. 1997 Feb;51(2):201-8. doi: 10.1124/mol.51.2.201.
• [12] An in vitro coculture system of human peripheral blood mononuclear cells with hepatocellular carcinoma-derived cells for predicting drug-induced liver injury. Arch Toxicol. 2021 Jan;95(1):149-168. doi: 10.1007/s00204-020-02882-4. Epub 2020 Aug 20.
• [13] Myocardial ischemia induces interleukin-6 and tissue factor production in patients with coronary artery disease: a dobutamine stress echocardiography study. Circulation. 2005 Nov 22;112(21):3272-9. doi: 10.1161/CIRCULATIONAHA.104.532259. Epub 2005 Nov 14.
• [14] Catecholamines suppress leptin release from in vitro differentiated subcutaneous human adipocytes in primary culture via beta1- and beta2-adrenergic receptors. Eur J Endocrinol. 2000 Sep;143(3):439-45. doi: 10.1530/eje.0.1430439.
• [15] Refining the human iPSC-cardiomyocyte arrhythmic risk assessment model. Toxicol Sci. 2013 Dec;136(2):581-94. doi: 10.1093/toxsci/kft205. Epub 2013 Sep 19.
• [16] Investigation of imatinib and other approved drugs as starting points for antidiabetic drug discovery with FXR modulating activity. Biochem Pharmacol. 2012 Jun 15;83(12):1674-81. doi: 10.1016/j.bcp.2012.02.027. Epub 2012 Mar 7.
• [17] Adenoviral gene transfer of Akt enhances myocardial contractility and intracellular calcium handling. Gene Ther. 2006 Jan;13(1):8-19. doi: 10.1038/sj.gt.3302589.
• [18] Kallikrein gene delivery improves cardiac reserve and attenuates remodeling after myocardial infarction. Hypertension. 2002 Nov;40(5):653-9. doi: 10.1161/01.hyp.0000036035.41122.99.
• [19] Left ventricular contractile effects of inducible nitric oxide synthase in the human allograft. Circulation. 1997 Nov 18;96(10):3436-42. doi: 10.1161/01.cir.96.10.3436.
• [20] Effect of 393T>C polymorphism of GNAS1 gene on dobutamine response in Chinese healthy subjects. J Clin Pharmacol. 2009 Aug;49(8):929-36. doi: 10.1177/0091270009337945. Epub 2009 Jun 19.
• [21] A bivariate functional mapping model for identifying haplotypes that control drug response for systolic and diastolic blood pressures. Pac Symp Biocomput. 2006:572-83.
• [22] Chronic phospholamban inhibition prevents progressive cardiac dysfunction and pathological remodeling after infarction in rats. J Clin Invest. 2004 Mar;113(5):727-36. doi: 10.1172/JCI18716.
• [23] Vitamin D signaling and the differentiation of developing dopamine systems. Neuroscience. 2016 Oct 1;333:193-203. doi: 10.1016/j.neuroscience.2016.07.020. Epub 2016 Jul 20.
• [24] 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.
• [25] Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52.
• [26] Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet. 2008;23(4):243-53.
• [27] SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med. 2013 Apr-Jun;34(2-3):360-72.
• [28] Chronic depolarization stimulates norepinephrine transporter expression via catecholamines. J Neurochem. 2006 May;97(4):1044-51.
• [29] SLC6A2 Gene (Protein Coding).
• [30] The effect of rare human sequence variants on the function of vesicular monoamine transporter 2. Pharmacogenetics. 2004 Sep;14(9):587-94. doi: 10.1097/00008571-200409000-00003.
• [31] Selective transport of monoamine neurotransmitters by human plasma membrane monoamine transporter and organic cation transporter 3. J Pharmacol Exp Ther. 2010 Dec;335(3):743-53. doi: 10.1124/jpet.110.170142. Epub 2010 Sep 21.
• [32] Familial orthostatic tachycardia due to norepinephrine transporter deficiency. Ann N Y Acad Sci. 2001 Jun;940:527-43. doi: 10.1111/j.1749-6632.2001.tb03703.x.
• [33] Role of protein kinase D1 in vasoconstriction and haemodynamics in rats. Microvasc Res. 2024 Mar;152:104627. doi: 10.1016/j.mvr.2023.104627. Epub 2023 Nov 12.
• [34] Targeting activation of specific NF-B subunits prevents stress-dependent atherothrombotic gene expression. Mol Med. 2012 Dec 20;18(1):1375-86. doi: 10.2119/molmed.2012.00282.
• [35] Inhibition of norepinephrine-induced cardiac hypertrophy in s100beta transgenic mice. J Clin Invest. 1998 Oct 15;102(8):1609-16. doi: 10.1172/JCI3077.
• [36] Norepinephrine stimulates calprotectin expression in human monocytic cells. J Periodontal Res. 2006 Jun;41(3):159-64. doi: 10.1111/j.1600-0765.2005.00845.x.
• [37] Quercetin-3-O-glucuronide inhibits noradrenaline-promoted invasion of MDA-MB-231 human breast cancer cells by blocking ?-adrenergic signaling. Arch Biochem Biophys. 2014 Sep 1;557:18-27. doi: 10.1016/j.abb.2014.05.030. Epub 2014 Jun 11.
• [38] Norepinephrine induces calcium spikes and proinflammatory actions in human hepatic stellate cells. Am J Physiol Gastrointest Liver Physiol. 2006 Nov;291(5):G877-84. doi: 10.1152/ajpgi.00537.2005. Epub 2006 Jun 15.
• [39] Cannabinoid Type 1 Receptors Are Upregulated During Acute Activation of Brown Adipose Tissue. Diabetes. 2018 Jul;67(7):1226-1236. doi: 10.2337/db17-1366. Epub 2018 Apr 12.
• [40] 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.
• [41] 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.
• [42] Substrates and inhibitors display different sensitivity to expression level of the dopamine transporter in heterologously expressing cells. J Neurochem. 2007 Apr;101(2):377-88. doi: 10.1111/j.1471-4159.2006.04384.x. Epub 2007 Jan 22.
• [43] Release and functional role of neuropeptide Y as a sympathetic modulator in human saphenous vein biopsies. Peptides. 2004 Jan;25(1):53-64. doi: 10.1016/j.peptides.2003.11.001.
• [44] Association between monoamine oxidase A activity in human male skin fibroblasts and genotype of the MAOA promoter-associated variable number tandem repeat. Hum Genet. 1999 Dec;105(6):542-51. doi: 10.1007/s004399900183.
• [45] Enzymatic characterization and interspecies difference of phenol sulfotransferases, ST1A forms. Drug Metab Dispos. 2001 Mar;29(3):274-81.
• [46] Increased arterial pressure in mice with overexpression of the ADHD candidate gene calcyon in forebrain. PLoS One. 2019 Feb 12;14(2):e0211903. doi: 10.1371/journal.pone.0211903. eCollection 2019.
• [47] Nesiritide: past, present, and future. Minerva Cardioangiol. 2005 Dec;53(6):509-22.