Target Information

Target General Information

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Target ID

T66237 (Former ID: TTDS00111)

Target Name

Vasopressin V2 receptor (V2R)

Synonyms

Renal-type arginine vasopressin receptor; DIR3; DIR; Antidiuretic hormone receptor; AVPR V2; ADHR

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Gene Name

AVPR2

Target Type

Successful target

[1]

Disease

[+] 6 Target-related Diseases

Acute diabete complication [ICD-11: 5A2Y]

Autism spectrum disorder [ICD-11: 6A02]

Enuresis [ICD-11: 6C00]

Hypo-osmolality/hyponatraemia [ICD-11: 5C72]

Pituitary gland disorder [ICD-11: 5A60-5A61]

Polyuria [ICD-11: MF55]

Function

The activity of this receptor is mediated by G proteins which activate adenylate cyclase. Involved in renal water reabsorption. Receptor for arginine vasopressin.

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BioChemical Class

GPCR rhodopsin

UniProt ID

V2R_HUMAN

Sequence

MLMASTTSAVPGHPSLPSLPSNSSQERPLDTRDPLLARAELALLSIVFVAVALSNGLVLA
ALARRGRRGHWAPIHVFIGHLCLADLAVALFQVLPQLAWKATDRFRGPDALCRAVKYLQM
VGMYASSYMILAMTLDRHRAICRPMLAYRHGSGAHWNRPVLVAWAFSLLLSLPQLFIFAQ
RNVEGGSGVTDCWACFAEPWGRRTYVTWIALMVFVAPTLGIAACQVLIFREIHASLVPGP
SERPGGRRRGRRTGSPGEGAHVSAAVAKTVRMTLVIVVVYVLCWAPFFLVQLWAAWDPEA
PLEGAPFVLLMLLASLNSCTNPWIYASFSSSVSSELRSLLCCARGRTPPSLGPQDESCTT
ASSSLAKDTSS

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3D Structure

Click to Show 3D Structure of This Target

AlphaFold

Drugs and Modes of Action

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Approved Drug(s)

[+] 4 Approved Drugs

Mozavaptan

Drug Info

Approved

Hyponatraemia

[3], [7], [8]

Oxytocin

Drug Info

Approved

Autism spectrum disorder

[9]

Tolvaptan

Drug Info

Approved

Hyponatraemia

[10], [11]

Vasopressin

Drug Info

Approved

Diabetes insipidus

[12], [13]

Clinical Trial Drug(s)

[+] 5 Clinical Trial Drugs

Lixivaptan

Drug Info

Phase 3

Hyponatraemia

[14], [15]

Satavaptan

Drug Info

Phase 3

Acute and chronic heart failure

[16], [17]

ASP-7035

Drug Info

Phase 2

Nocturia

[19]

SSR149415

Drug Info

Phase 2

Anxiety disorder

[20], [21], [22]

VA-106483

Drug Info

Phase 2

Nocturia

[23]

Discontinued Drug(s)

[+] 4 Discontinued Drugs

OPC-51803

Drug Info

Discontinued in Phase 1

Urinary incontinence

[24], [25]

OX 19

Drug Info

Discontinued in Phase 1

Urinary incontinence

[26]

VNA-932

Drug Info

Discontinued in Phase 1

Urinary incontinence

[27], [28]

JTV-605

Drug Info

Terminated

Dysmenorrhea

[29]

Mode of Action

[+] 3 Modes of Action

Inhibitor

[+] 22 Inhibitor drugs

Mozavaptan

Drug Info

[30], [31], [32], [33]

ATOSIBAN

Drug Info

[36]

SSR149415

Drug Info

[40]

VA-106483

Drug Info

[41]

ARGENINE VASOPRESSIN

Drug Info

[45]

D(CH2)5[Tyr(Me)2,Thr4,Orn8,Tyr9-NH2]VT

Drug Info

[47]

D[Arg4,Lys8]VP

Drug Info

[45]

D[Arg4,Orn8]VP

Drug Info

[45]

D[Arg4]AVP

Drug Info

[45]

D[Cha4,Dab8]VP

Drug Info

[45]

D[Cha4,Dap8]VP

Drug Info

[45]

D[Cha4,Lys8]VP

Drug Info

[45]

D[Cha4,Orn8]VP

Drug Info

[45]

D[Cha4]AVP

Drug Info

[45]

D[D-3-Pal2]AVP

Drug Info

[45]

D[Leu4,Dab8]VP

Drug Info

[45]

D[Leu4,Dap8]VP

Drug Info

[45]

D[Leu4,Lys8]VP

Drug Info

[45]

D[Leu4]AVP

Drug Info

[45]

D[Orn4,Lys8]VP

Drug Info

[45]

L-372662

Drug Info

[48]

YM-35278

Drug Info

[51]

Agonist

[+] 7 Agonist drugs

Oxytocin

Drug Info

[34]

Vasopressin

Drug Info

[1]

ASP-7035

Drug Info

[39]

OPC-51803

Drug Info

[42]

OX 19

Drug Info

[43]

VNA-932

Drug Info

[44], [3]

[Val4]AVP

Drug Info

[52]

Antagonist

[+] 11 Antagonist drugs

Tolvaptan

Drug Info

[35], [11]

Lixivaptan

Drug Info

[37]

Satavaptan

Drug Info

[17], [32], [38]

JTV-605

Drug Info

[30]

CL-385004

Drug Info

[30]

d(CH2)5[D-Ile2,Ile4]AVP

Drug Info

[46]

d(CH2)5[Tyr(Me)2]AVP

Drug Info

[46]

d[Pen1,Tyr(Me)2]AVP

Drug Info

[46]

FR161282

Drug Info

[30]

YM 218

Drug Info

[49]

YM 471

Drug Info

[50]

Cell-based Target Expression Variations

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Cell-based Target Expression Variations

Cell-based Target Expression Variations Info

Different Human System Profiles of Target	Top
Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target. A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020). Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function. Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006). Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database. The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017). Human Similarity Proteins Human Pathway Affiliation Biological Network Descriptors

Different Human System Profiles of Target

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Human Similarity Proteins of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.

A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs (Brief Bioinform, 21: 649-662, 2020).

Human Pathway Affiliation of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.

Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes (Pharmacol Rev, 58: 259-279, 2006).

Biological Network Descriptors of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.

The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information (Front Pharmacol, 9, 1245, 2018; Curr Opin Struct Biol. 44:134-142, 2017).

Human Similarity Proteins

Human Pathway Affiliation

Biological Network Descriptors

Protein Name	Pfam ID	Percentage of Identity (%)	E value
Olfactory receptor 4A15 (OR4A15)	PF13853	22.671 (73/322)	4.15E-07
Olfactory receptor 9G4 (OR9G4)	PF13853	32.292 (31/96)	1.19E-05
Olfactory receptor 4K3 (OR4K3)	PF13853	24.201 (53/219)	1.34E-04
Olfactory receptor 4K17 (OR4K17)	PF13853	21.121 (49/232)	1.58E-04
Olfactory receptor 2A5 (OR2A5)	PF13853	21.429 (72/336)	4.10E-04
Olfactory receptor 1L3 (OR1L3)	PF13853	23.715 (60/253)	6.90E-04
Olfactory receptor 2A25 (OR2A25)	PF13853	22.963 (31/135)	7.69E-04
Olfactory receptor 2A14 (OR2A14)	PF13853	21.586 (49/227)	1.00E-03
Olfactory receptor 4K5 (OR4K5)	PF13853	24.204 (38/157)	1.00E-03
Olfactory receptor 2A12 (OR2A12)	PF13853	25.397 (32/126)	1.00E-03
Olfactory receptor 4C11 (OR4C11)	PF13853	23.392 (40/171)	1.00E-03
Olfactory receptor 5M1 (OR5M1)	PF13853	26.446 (32/121)	2.00E-03
Olfactory receptor 9Q2 (OR9Q2)	PF13853	30.097 (31/103)	2.00E-03
Olfactory receptor 56B1 (OR56B1)	PF13853	28.947 (22/76)	3.00E-03
Olfactory receptor 5M10 (OR5M10)	PF13853	25.620 (31/121)	4.00E-03
Olfactory receptor 8D2 (OR8D2)	PF13853	28.571 (22/77)	5.00E-03
Olfactory receptor 2T29 (OR2T29)	PF13853	32.432 (36/111)	5.00E-03
Olfactory receptor 2T5 (OR2T5)	PF13853	32.432 (36/111)	5.00E-03
Click to Show/Hide the Information of Human Similarity Proteins

KEGG Pathway	Pathway ID	Affiliated Target
Phospholipase D signaling pathway	hsa04072	Affiliated Target
Class: Environmental Information Processing => Signal transduction	Pathway Hierarchy
Neuroactive ligand-receptor interaction	hsa04080	Affiliated Target
Class: Environmental Information Processing => Signaling molecules and interaction	Pathway Hierarchy
Vasopressin-regulated water reabsorption	hsa04962	Affiliated Target
Class: Organismal Systems => Excretory system	Pathway Hierarchy

Degree	5	Degree centrality	5.37E-04	Betweenness centrality	3.84E-04
Closeness centrality	2.07E-01	Radiality	1.36E+01	Clustering coefficient	2.00E-01
Neighborhood connectivity	2.46E+01	Topological coefficient	2.78E-01	Eccentricity	12
Download	Click to Download the Full PPI Network of This Target

Chemical Structure based Activity Landscape of Target

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Drug Property Profile of Target

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(1) Molecular Weight (mw) based Drug Clustering

(2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering

(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering

(4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering

(5) Rotatable Bond Count (rotbonds) based Drug Clustering

(6) Topological Polar Surface Area (polararea) based Drug Clustering

"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five

Co-Targets

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Co-Targets

Co-Targets Info

Target Poor or Non Binders

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Target Poor or Non Binders

Target Poor or Non Binders Info

Target Affiliated Biological Pathways

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KEGG Pathway

[+] 2 KEGG Pathways

Neuroactive ligand-receptor interaction

Vasopressin-regulated water reabsorption

Pathwhiz Pathway

[+] 1 Pathwhiz Pathways

Vasopressin Regulation of Water Homeostasis

PID Pathway

[+] 1 PID Pathways

Arf6 trafficking events

Reactome

[+] 3 Reactome Pathways

Vasopressin-like receptors

G alpha (s) signalling events

Vasopressin regulates renal water homeostasis via Aquaporins

WikiPathways

[+] 5 WikiPathways

GPCRs, Class A Rhodopsin-like

Regulation of Water Balance by Renal Aquaporins

Peptide GPCRs

GPCR ligand binding

GPCR downstream signaling

Target-Related Models and Studies

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Target Validation

Target Validation Info

References

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REF 1

Vasopressin receptors: structure/function relationships and signal transduction in target cells. J Soc Biol. 2005;199(4):351-9.

REF 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: 2182).

REF 3

Drugs@FDA. U.S. Food and Drug Administration. U.S. Department of Health & Human Services. 2015

REF 4

ClinicalTrials.gov (NCT00748072) 1-deamino 8-d-arginine Vasopressin (DDAVP) in Percutaneous Ultrasound-guided Renal Biopsy. U.S. National Institutes of Health.

REF 5

REF 6

Emerging diuretics for the treatment of heart failure. Expert Opin Emerg Drugs. 2009 Mar;14(1):195-204.

REF 7

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800001739)

REF 8

REF 9

REF 10

REF 11

Hughes B: 2009 FDA drug approvals. Nat Rev Drug Discov. 2010 Feb;9(2):89-92.

REF 12

REF 13

New topics in vasopressin receptors and approach to novel drugs: research and development of conivaptan hydrochloride (YM087), a drug for the treatment of hyponatremia. J Pharmacol Sci. 2009 Jan;109(1):53-9.

REF 14

REF 15

Physical state of kappa-carrageenan modulates the mode of action of kappa-carrageenase from Pseudoalteromonas carrageenovora. Biochem J. 2009 May 1;419(3):545-53.

REF 16

REF 17

Post-translational import of protein into the endoplasmic reticulum of a trypanosome: an in vitro system for discovery of anti-trypanosomal chemical entities. Biochem J. 2009 Apr 15;419(2):507-17.

REF 18

ClinicalTrials.gov (NCT01179607) Study of Efficacy of a Vasopressin 2 Receptor Antagonist M0002 for Treatment of Ascites in Cirrhotic Subjects With Hypo- or Normonatraemia. U.S. National Institutes of Health.

REF 19

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030285)

REF 20

REF 21

Anxiolytic- and antidepressant-like effects of the non-peptide vasopressin V1b receptor antagonist, SSR149415, suggest an innovative approach for t... Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6370-5.

REF 22

Novel drugs and therapeutic targets for severe mood disorders. Neuropsychopharmacology. 2008 Aug;33(9):2080-92.

REF 23

ClinicalTrials.gov (NCT01038843) Efficacy Study of VA106483 in Males With Nocturia.. U.S. National Institutes of Health.

REF 24

REF 25

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010599)

REF 26

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800021110)

REF 27

REF 28

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800013621)

REF 29

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800010443)

REF 30

Nonpeptide vasopressin receptor antagonists: development of selective and orally active V1a, V2 and V1b receptor ligands. Prog Brain Res. 2002;139:197-210.

REF 31

Effects of an oral vasopressin receptor antagonist (OPC-31260) in a dog with syndrome of inappropriate secretion of antidiuretic hormone. Aust Vet J. 2000 Dec;78(12):825-30.

REF 32

Nonpeptide vasopressin antagonists: a new group of hormone blockers entering the scene. Exp Clin Endocrinol Diabetes. 1999;107(3):157-65.

REF 33

New analgesic drugs derived from phencyclidine. J Med Chem. 1981 May;24(5):496-9.

REF 34

REF 35

Antibody-mediated disruption of the interaction between PCSK9 and the low-density lipoprotein receptor. Biochem J. 2009 May 1;419(3):577-84.

REF 36

The discovery of GSK221149A: a potent and selective oxytocin antagonist. Bioorg Med Chem Lett. 2008 Jan 1;18(1):90-4.

REF 37

Emerging drugs for acute and chronic heart failure: current and future developments. Expert Opin Emerg Drugs. 2007 Mar;12(1):75-95.

REF 38

Vasopressin-induced von Willebrand factor secretion from endothelial cells involves V2 receptors and cAMP. J Clin Invest. 2000 Jul;106(1):107-16.

REF 39

Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030285)

REF 40

Tetrahydroquinoline sulfonamides as vasopressin 1b receptor antagonists. Bioorg Med Chem Lett. 2009 Nov 1;19(21):6018-22.

REF 41

New benzylureas as a novel series of potent, nonpeptidic vasopressin V2 receptor agonists. J Med Chem. 2008 Dec 25;51(24):8124-34.

REF 42

Effects of OPC-51803, a novel, nonpeptide vasopressin V2-receptor agonist, on micturition frequency in Brattleboro and aged rats. J Pharmacol Sci. 2003 Dec;93(4):484-8.

REF 43

Investigation of mechanism of desmopressin binding in vasopressin V2 receptor versus vasopressin V1a and oxytocin receptors: molecular dynamics simulation of the agonist-bound state in the membrane-aqueous system. Biopolymers. 2006 Apr 5;81(5):321-38.

REF 44

Biased Agonist Pharmacochaperones of the AVP V2 Receptor May Treat Congenital Nephrogenic Diabetes Insipidus. J Am Soc Nephrol. 2009 October; 20(10): 2190-2203.

REF 45

Design and synthesis of the first selective agonists for the rat vasopressin V(1b) receptor: based on modifications of deamino-[Cys1]arginine vasop... J Med Chem. 2007 Feb 22;50(4):835-47.

REF 46

Binding properties of a selective tritiated vasopressin V2 receptor antagonist, [H]-SR 121463. Kidney Int. 2000 Oct;58(4):1613-22.

REF 47

Synthesis and characterization of fluorescent antagonists and agonists for human oxytocin and vasopressin V(1)(a) receptors. J Med Chem. 2002 Jun 6;45(12):2579-88.

REF 48

Oral oxytocin antagonists. J Med Chem. 2010 Sep 23;53(18):6525-38.

REF 49

Effects of YM218, a nonpeptide vasopressin V1A receptor-selective antagonist, on human vasopressin and oxytocin receptors. Pharmacol Res. 2005 Mar;51(3):275-81.

REF 50

Effects of YM471, a nonpeptide AVP V(1A) and V(2) receptor antagonist, on human AVP receptor subtypes expressed in CHO cells and oxytocin receptors in human uterine smooth muscle cells. Br J Pharmacol. 2001 Jul;133(5):746-54.

REF 51

Preparation of (4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide derivatives as novel arginine vasopressin V(2) receptor agonists. Bioorg Med Chem. 2008 Nov 1;16(21):9524-35.

REF 52

[1-deamino-4-cyclohexylalanine] arginine vasopressin: a potent and specific agonist for vasopressin V1b receptors. Endocrinology. 2002 Dec;143(12):4655-64.

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