Details of the Drug Combination

General Information of Drug Combination (ID: DCE22ZE)

• Drug Combination Name: Norepinephrine + Terlipressin
• Indication: Safety and Efficacy of Terlipressin and Noradrenaline and Predictive Factors of Response in Type 2 HRS; Status: Phase 1 [1]
• Component Drugs:
  Norepinephrine (DMOUC09): Small molecular drug
  Terlipressin (DMT9FH3): Small molecular drug

Molecular Interaction Atlas of This Drug Combination

Indication(s) of Norepinephrine

Disease Entry	ICD 11	Status	REF
Alopecia	ED70	Approved	[2]
Bronchiectasis	CA24	Approved	[2]
Bronchitis	CA20	Approved	[2]
Chronic fatigue syndrome	8E49	Approved	[2]
Depression	6A70-6A7Z	Approved	[2]
Psychosexual disorder	N.A.	Approved	[2]
Pulmonary emphysema	CA21.Z	Approved	[2]
Pure autonomic failure	N.A.	Approved	[2]
Radiodermatitis	N.A.	Approved	[2]
Sepsis	1G40-1G41	Approved	[3]
Severe asthma	CA23	Approved	[2]
Asthma	CA23	Investigative	[2]

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	[6]

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	[7]
Organic cation transporter 3 (SLC22A3)	DT6201N	S22A3_HUMAN	Substrate	[7]
Organic cation transporter 1 (SLC22A1)	DTT79CX	S22A1_HUMAN	Substrate	[8]
Vesicular amine transporter 2 (SLC18A2)	DTT7VPB	VMAT2_HUMAN	Substrate	[9]
Vesicular amine transporter 1 (SLC18A1)	DTM953D	VMAT1_HUMAN	Substrate	[9]
Sodium-dependent noradrenaline transporter (SLC6A2)	DT9JBVI	SC6A2_HUMAN	Substrate	[10]
Sodium- and chloride-dependent glycine transporter 2 (SLC6A5)	DTE8R17	SC6A5_HUMAN	Substrate	[11]

Norepinephrine Interacts with 17 DOT Molecule(s)

DOT Name	DOT ID	UniProt ID	Mode of Action	REF
Solute carrier family 22 member 3 (SLC22A3)	OTQYGVXX	S22A3_HUMAN	Increases Uptake	[12]
Protein phosphatase 1 regulatory subunit 12A (PPP1R12A)	OT4AVU95	MYPT1_HUMAN	Increases Phosphorylation	[13]
Superoxide dismutase , mitochondrial (SOD2)	OTIWXGZ9	SODM_HUMAN	Increases Expression	[14]
Protein S100-B (S100B)	OTHHDS33	S100B_HUMAN	Increases Expression	[15]
Protein S100-A8 (S100A8)	OTVMOB3F	S10A8_HUMAN	Increases Expression	[16]
Myosin light chain 1/3, skeletal muscle isoform (MYL1)	OTDUYR4U	MYL1_HUMAN	Increases Phosphorylation	[13]
Protein S100-A9 (S100A9)	OTOARHCS	S10A9_HUMAN	Increases Expression	[16]
Beta-2 adrenergic receptor (ADRB2)	OTSDOX4Q	ADRB2_HUMAN	Affects Binding	[17]
C-C motif chemokine 5 (CCL5)	OTSCA5CK	CCL5_HUMAN	Increases Secretion	[18]
Nuclear factor NF-kappa-B p105 subunit (NFKB1)	OTNRRD8I	NFKB1_HUMAN	Affects Localization	[14]
Alpha-1D adrenergic receptor (ADRA1D)	OTW2CD1O	ADA1D_HUMAN	Affects Binding	[19]
Alpha-1A adrenergic receptor (ADRA1A)	OTUIWCL5	ADA1A_HUMAN	Affects Binding	[20]
Transcription factor p65 (RELA)	OTUJP9CN	TF65_HUMAN	Affects Localization	[14]
Sodium-dependent dopamine transporter (SLC6A3)	OT39XG28	SC6A3_HUMAN	Increases Uptake	[21]
Pro-neuropeptide Y (NPY)	OT4ICV3P	NPY_HUMAN	Affects Response To Substance	[22]
Natriuretic peptides B (NPPB)	OTSN2IPY	ANFB_HUMAN	Decreases Abundance	[23]
Equilibrative nucleoside transporter 4 (SLC29A4)	OTWTZXMX	S29A4_HUMAN	Increases Uptake	[12]

Indication(s) of Terlipressin

Disease Entry	ICD 11	Status	REF
Hypertension	BA00-BA04	Approved	[4]

Terlipressin Interacts with 1 DTT Molecule(s)

DTT Name	DTT ID	UniProt ID	Mode of Action	REF
Vasopressin V1a receptor (V1AR)	TT4TFGN	V1AR_HUMAN	Stimulator	[24]

References

• [1] ClinicalTrials.gov (NCT01637454) TYPE 2 HEPATORENAL SYNDROME
• [2] Norepinephrine FDA Label
• [3] 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).
• [4] Pharmacology, clinical efficacy and safety of terlipressin in esophageal varices bleeding, septic shock and hepatorenal syndrome. Expert Rev Gastroenterol Hepatol. 2007 Dec;1(2):207-17.
• [5] 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.
• [6] 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.
• [7] Differential pharmacological in vitro properties of organic cation transporters and regional distribution in rat brain. Neuropharmacology. 2006 Jun;50(8):941-52.
• [8] Organic cation transporters and their pharmacokinetic and pharmacodynamic consequences. Drug Metab Pharmacokinet. 2008;23(4):243-53.
• [9] SLC18: Vesicular neurotransmitter transporters for monoamines and acetylcholine. Mol Aspects Med. 2013 Apr-Jun;34(2-3):360-72.
• [10] Chronic depolarization stimulates norepinephrine transporter expression via catecholamines. J Neurochem. 2006 May;97(4):1044-51.
• [11] SLC6A2 Gene (Protein Coding).
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Inhibition of norepinephrine-induced cardiac hypertrophy in s100beta transgenic mice. J Clin Invest. 1998 Oct 15;102(8):1609-16. doi: 10.1172/JCI3077.
• [16] 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.
• [17] 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.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.
• [22] 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.
• [23] Nesiritide: past, present, and future. Minerva Cardioangiol. 2005 Dec;53(6):509-22.
• [24] Investigational vasopressin receptor modulators in the pipeline. Expert Opin Investig Drugs. 2009 Aug;18(8):1119-31.