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UT receptor

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Target not currently curated in GtoImmuPdb

Target id: 365

Nomenclature: UT receptor

Family: Urotensin receptor

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 389 17q25.3 UTS2R urotensin 2 receptor 2
Mouse 7 385 11 E2 Uts2r urotensin 2 receptor 25
Rat 7 386 10q32.3 Uts2r urotensin 2 receptor 45,60
Previous and Unofficial Names Click here for help
GPR14 [2,45] | UII-R1 | UTR2 | G protein-coupled receptor 14 | urotensin II receptor | SENR (sensory epithelial neuropeptide-like receptor) [60]
Database Links Click here for help
Specialist databases
GPCRDB ur2r_human (Hs), ur2r_mouse (Mm), ur2r_rat (Rn)
Other databases
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands Click here for help
urotensin-II {Sp: Human} , urotensin-II {Sp: Mouse} , urotensin-II {Sp: Rat}
urotensin II-related peptide {Sp: Human, Mouse, Rat}
Comments: aka GPR14

Download all structure-activity data for this target as a CSV file go icon to follow link

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
urotensin II-related peptide {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Hs Full agonist 9.6 pKd 24,58
pKd 9.6 (Kd 2.4x10-10 M) [24,58]
[125I]U-II (human) Peptide Ligand is labelled Ligand is radioactive Hs Full agonist 9.4 – 9.6 pKd 2,11,44
pKd 9.4 – 9.6 (Kd 4x10-10 – 2.4x10-10 M) [2,11,44]
[125I]U-II (human) Peptide Ligand is labelled Ligand is radioactive Mm Full agonist 9.2 pKd 25
pKd 9.2 [25]
[125I]U-II (human) Peptide Ligand is labelled Ligand is radioactive Rn Full agonist 9.2 pKd 2
pKd 9.2 [2]
[Pen5]U-(4-11) (human) Peptide Hs Full agonist 9.7 pKi 29
pKi 9.7 [29]
U-II-(4-11) (human) Peptide Hs Full agonist 9.6 pKi 29
pKi 9.6 [29]
[Bz-Phe6]U-II (human) Peptide Hs Full agonist 9.1 pKi 7
pKi 9.1 [7]
urotensin-II {Sp: Mouse} Peptide Rn Full agonist 8.8 pKi 19
pKi 8.8 [19]
urotensin-II {Sp: Rat} Peptide Ligand is endogenous in the given species Rn Full agonist 8.8 pKi 19
pKi 8.8 [19]
urotensin-II {Sp: Human} Peptide Rn Full agonist 8.7 pKi 19
pKi 8.7 [19]
urotensin-II {Sp: Human} Peptide Ligand is endogenous in the given species Hs Full agonist 8.6 pKi 2,42,47,49
pKi 8.6 [2,42,47,49]
urotensin-II {Sp: Human} Peptide Mm Full agonist 8.2 – 9.0 pKi 19,25
pKi 8.2 – 9.0 [19,25]
urotensin-II {Sp: Rat} Peptide Mm Full agonist 8.6 pKi 19,25
pKi 8.6 [19,25]
urotensin-II {Sp: Mouse} Peptide Hs Full agonist 8.5 pKi 19
pKi 8.5 [19]
urotensin-II {Sp: Mouse} Peptide Ligand is endogenous in the given species Mm Full agonist 8.4 – 8.6 pKi 19,25
pKi 8.4 – 8.6 [19,25]
urotensin-II {Sp: Rat} Peptide Hs Full agonist 8.5 pKi 19
pKi 8.5 [19]
AC-7954 Small molecule or natural product Hs Full agonist 6.6 pKi 15,39
pKi 6.6 [15,39]
[3-iodo-Tyr6]U-II-(4-11) (human) Peptide Hs Agonist 8.7 pEC50 36
pEC50 8.7 [36]
Urolinin Peptide Hs Agonist 8.3 pEC50 3
pEC50 8.3 [3]
FL104 Small molecule or natural product Hs Full agonist 5.8 – 7.5 pEC50 38,40
pEC50 5.8 – 7.5 [38,40]
urotensin II-related peptide {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Hs Full agonist 8.6 pIC50 59
pIC50 8.6 [59]
View species-specific agonist tables
Agonist Comments
Extensive SAR studies performed with U-II isopeptides emphasize the importance of the cyclic hexapeptide core of U-II [8,27,35-36]. Modifications of the exocyclic structure of U-II (e.g. amino terminus truncations, amidation) generally have only minor effects on UT affinity (consistent with the divergent amino-terminus/conservation of the carboxyl-octapeptide motif in U-II across species and the observation that human, goby, rat, mouse and pig U-II isopeptides are equipotent ligands at rodent and primate UT receptors). Indeed, hU-II(4-11) is typically ~3-fold more potent as a UT ligand compared to the parent peptide.

In contrast, disruption of the cyclic structure of U-II (e.g. [Ala5, 10], [Ser5,10], [Cys(Acm)5,10] analogs, D-Cys substitutions etc.) results in a profound loss in UT affinity [27,36]. [Cys5] substitution with penicillamine b,b-dimethylcysteine ([Pen5]hU-II(4-11)), however, stabilizes the cyclic structure of the truncated U-II analogue and is reported to enhance UT affinity ~3-fold [29].

Endocyclic modifications (e.g. D-substitutions, Ala-scan, single residue deletions) of Phe6, Trp7, Lys8 or Tyr9 have profound effects on ligand affinity for UT [8,27,35-36]. Such observations, coupled with pharmacophore modeling approaches (NMR studies, virtual compound bank screening), have lead to the identification of weak, nonpeptidic UT antagonists as described below e.g. S6716 [27]. Alternatively, weak, nonpeptide agonists (e.g. AC-7954) have also been identified using high throughput screening approaches [15].

[Bz-Phe6]hU-II (a high affinity, full agonist) has been used successfully as a photo-affinity label for rat UT where mutagenesis studies have demonstrated a ligand interaction with Met184/185 in TM4 of rat UT [7].

Several "nonselective" UT agonists have been identified. UT exhibits highest sequence homology (albeit ~27%) with somatostatin (SST4) receptors. Consequently, somatostatin analogues (SB-710411 and lanreotide, but not somatostatin itself) have been shown to be "nonselective" rodent and primate UT ligands [5,31]. Such an observation is interesting since these peptide analogues share some sequence homology with the conserved hexapeptide motif in the U-II isopeptide family, that required in U-II isopeptides for retention of UT receptor affinity. Similarly, BIM-23042, a neuromedin-B ligand, also shows a somewhat similar structure and also exhibits UT affinity [31]. Interestingly, however, such ligands are full agonists at human and monkey UT but are either partial agonists (murine UT) or antagonists (rat UT) at primate UT receptors (partial agonism may account, in part, for the functional antagonism seen with [Orn8]hU-II in the rat aorta [10]).

It is now recognized that the mammalian genome encodes for more than one "urotensin-II-like" peptide with the recent identification of URP, "urotensin-related peptide" (Ac[CFWKYC]V) by Sugo et al. (rat, mouse and human URP prepropeptides contain 113-119 amino acids; [59]]). Consistent with existing SAR data, this octapeptide fragment appears to exert similar pharmacodynamic actions as mature U-II. Preliminary inspection suggests that human URP is encoded on chromosome 3q29.
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
4-Cl-cinnamoyl-c[DCys-4Pal-DTrp-Orn-Val-Cys]-His-amide Peptide Hs Inverse agonist 8.4 pKd 14
pKd 8.4 [14]
tolyacetyl-c[DCys-Apa-DTrp-Orn-Val-Cys]-His-amide Peptide Hs Antagonist 7.7 pKd 14
pKd 7.7 [14]
BIM 23127 Peptide Hs Antagonist 6.7 pKd 30
pKd 6.7 [30]
compound 1a [PMID: 18573659] Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.4 pKi 33
pKi 8.4 (Ki 4x10-9 M) [33]
Description: Ligand binding.
JNJ-39319202 Small molecule or natural product Hs Antagonist 8.4 pKi 37
pKi 8.4 (Ki 4x10-9 M) [37]
SB-706375 Small molecule or natural product Hs Antagonist 8.0 pKi 19
pKi 8.0 [19]
SB-706375 Small molecule or natural product Mm Antagonist 7.7 pKi 19
pKi 7.7 [19]
SB-706375 Small molecule or natural product Rn Antagonist 7.7 pKi 19
pKi 7.7 [19]
[Orn5]URP Peptide Rn Antagonist 7.2 pKi 17
pKi 7.2 (Ki 6.77x10-8 M) [17]
SB-436811 Small molecule or natural product Rn Antagonist 6.7 pKi 34
pKi 6.7 [34]
SB-611812 Small molecule or natural product Hs Antagonist 6.6 pKi 52
pKi 6.6 [52]
[Cha6]U-II-(4-11) Peptide Rn Antagonist 6.4 pKi 11
pKi 6.4 [11]
DS37001789 Small molecule or natural product Hs Antagonist 9.1 pIC50 48
pIC50 9.1 (IC50 9x10-10 M) [48]
RCI-0879 Small molecule or natural product Hs Antagonist 9.0 pIC50 62
pIC50 9.0 (IC50 1x10-9 M) [62]
Description: Determined in a hUT binding assay
SR101099 Small molecule or natural product Hs Antagonist 8.0 pIC50 50
pIC50 8.0 (IC50 1.01x10-8 M) [50]
palosuran Small molecule or natural product Hs Antagonist 7.1 pIC50 13
pIC50 7.1 [13]
S6716 Small molecule or natural product Hs Inverse agonist 6.4 pIC50 27
pIC50 6.4 [27]
View species-specific antagonist tables
Antagonist Comments
Following detailed SAR studies using a variety of U-II analogues [8,27,35-36], several groups have focused on modifying the cyclic hexapeptide core of the U-II isopeptide family in an attempt to generate UT antagonists. In addition, several somatostatin derivatives were modified to generate weak, non-selective functional UT receptor antagonists such as SB-710411 [5] and PRL-2903 [53].

Recently, significant improvements in both UT receptor potency and selectivity have been made in such somatostatin derivatives following Lys/Orn subsitutions (as was seen in [Orn8]hU-II [10]) and by placing various arylacylating groups on the amino-terminus of the peptide ring e.g. 4-Cl-cinnamoyl-c[DCys-4Pal-DTrp-Orn-Val-Cys]-His-amide is a 4nM ligand and human and rat UT whereas tolylacetyl-c[DCys-Apa-DTrp-Orn-Val-Cys]-His-amide appears to exhibit selectivity for the rat UT receptor (19nM) over the human homologue (246nM) [14]. Little is known, however, about the selectivity of these ligands against other G-protein-coupled receptors.

Although BIM-23127 is a neuromedin-B ligand and, therefore, not considered to be "selective" as a U-II antagonist, it is a relatively potent ligand at rat UT and human UT (20-30nM pA2 against hU-II-induced Ca2+-mobilization) [30].

Using an NMR-based/virtual screening approach, S6716 has been identified as a weak UT receptor antagonist with an IC50 of ~400nM [27]. Indeed, several publications are beginning to appear in the patent literature claiming the identification of potent, selective nonpeptidic antagonists [16,20-21]. However, as for the indole derivative S6716, to date, little detailed pharmacological information is available on such moieties such as selectivity, nature of antagonism (competitive versus insurmountable), rodent versus primate UT receptor affinities etc. [16,20-21].

Urantide, [Pen5,DTrp7,Orn8]hU-II(4-11), is a recently described potent and selective peptidic UT receptor antagonist (high affinity ligand with a pKi8.3). Urantide blocks hU-II-induced contractions in the rat aorta without altering those induced by noradrenaline or endothelin-1 [51]. Although functional antagonism has been demonstrated at the rat UT, its should be noted that, to date, no such property has been ascribed for urantide at the primate receptor i.e. urantide is a potent human UT ligand but functional characterization e.g. inhibition of Ca2+-mobilization) has not been performed. As such, a lack of intrinsic activity remains to be established at the primate UT receptor and caution should be used when evaluating urantide in human and monkey systems (poor receptor density/signal transduction coupling in recombinant cell based assay systems can make partial agonists with low intrinsic activity erreneosuly appear to behave as antagonists [10]).
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
[125I]N-biotin-[Ahx0, Bpa3]U-II (human) Peptide Ligand is labelled Ligand is radioactive Hs - - - 18
[18]
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gq/G11 family Phospholipase C stimulation
Comments:  To date, relatively little research has focusd on urotensin-II signaling and specific G-protein-coupling pathways. Signaling events are associated with phospholipase C-mediated increases in [Ca2+] consistent with Gq/G11 coupling [43]. Indeed, urotensin-II/LDL-induced vascular smooth muscle proliferation is inhibited in part by inhibition of Gq (with anti-Gq/G11α antibodies, although the inhibition was of the synergistic actions of urotensin-II with LDL and not urotensin-II alone [64]). In similar assays, inhibition of Gαq (dominant negative antisense delivered by adenovirus) attenuates urotensin-II-mediated cardiac myocyte hypertrophy in vitro (although, notably, inhibition was only partial [63]). Such data is of interest since it has been observed that urotensin-II-mediated signal transduction (ERK-activation) is also sensitive to pertussis toxin, albeit in recombinant CHO cells expressing human UT (suggestive of a role for Gi/o [67]). In intact tissues such as the rabbit isolated aorta, U-II-mediated vasoconstriction is associated with phospholipase-C mediated Ca2+/inositol signaling in accord with cell based assays depicting a major role for Gq in mediating the cellular actions of urotensin-II [55]. Such activity is also coupled to protein kinase C [53], [64] although this may differ in rat spinal neurons where [Ca2+]-mobilization is associated with protein kinase-A activation [26]).

References:  43,55,63-64,67
Tissue Distribution Click here for help
Multiple approaches have demonstrated that human UT expression is relatively ubiquitous with mRNA and protein being documented in (but not limited to) heart (cardiomyocytes, fibroblasts), arteries (endothelium, vascular smooth muscle, atheroma), kidney, skeletal muscle and CNS.
Species:  Human
Technique:  PCR, Northern blot analysis, radioligand binding
References:  2,25,44
Murine UT cDNA transcripts (PCR) are present within cardiac and vascular (thoracic but not abdominal aorta) tissue in addition to bladder and pancreas. Trace levels of expression are also observed in skeletal muscle, oesophagus, lung and adipose tissue.
Species:  Mouse
Technique:  PCR.
References:  2,23,25,45,60
A similar pattern of expression to that of the mouse is seen within major cardiovascular tissue along with the CNS and sensory epithelia, spleen, kidney, ovary, lung and liver.
Species:  Rat
Technique:  PCR.
References:  2,23,25,45,60
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Intracellular [Ca2+]i - levels elevated in response to exogenous U-II in intact HEK 293 cells.
Species:  Mouse
Tissue:  HEK 293 cells expressing recombinant UT receptors.
Response measured:  Intracellular Ca2+ concentrations measured by fluorescence of fura-2/AM
References:  25,42,47,49
U-II stimulated in time- and dose-dependent manners, the phosphorylation level of ERK. Urotensin II-induced proliferation of VSMCs was inhibited by ERK kinase inhibitor PD98059
Species:  Rat
Tissue:  Cultured vascular smooth muscle cells (VSMC) from adult rat aorta
Response measured:  Extracellular signal-regulated kinase (ERK) activation
References:  61
Recombinant cell-based functional assays: intracellular signal transduction
Species:  Human
Tissue:  Recombinant HEK-293 cells
Response measured:  Intracellular signal transduction e.g. [Ca2+]-mobilization
References:  2
ERK activation in transfected CHO cells
Species:  Human
Tissue:  CHO cells expressing cloned receptor
Response measured:  Activation of extracellular signal-regulated kinase 1/2 (ERK1/2)
References:  67
U-II induced [Ca2+]i increases in spinal cord neurons with a threshold of 10-9M, and a maximal effect at 10-6
Species:  Rat
Tissue:  Dissociated cultures of spinal cord neurons from newborn rats
Response measured:  Intracellular Ca2+ concentrations measured by fluorescence of fura 2-AM
References:  26
U-II dose depenantly activated ERKs and induced expression of specific genes encoding atrial natriuretic peptide and brain natriuretic peptide. This significantly incresed amino acid incorporation into proteins and increased cell size and myofibril organisation.
Species:  Rat
Tissue:  Cultured cardiomyocytes from neonatal rats
Response measured:  Extracellular signal-regulated kinase (ERK) activation
References:  68
U-II induced smooth muscle contraction was inhibited by the Rho-kinase inhibitor Y-27632 and by a membrane-permeant RhoA inhibitor (TAT-C3).
Species:  Rat
Tissue:  Endothelium-denuded rings of adult rat aorta
Response measured:  Smooth muscle contraction
References:  56
Physiological Functions Click here for help
Regulation of locomotor function.
Species:  Mouse
Tissue:  In vivo.
References:  12
Cardiac contractility.
Species:  Human
Tissue:  Isolated right atrial trabeculae.
References:  54
Vasoconstriction.
Species:  Rat
Tissue:  Isolated aortic ring contraction.
References:  2,23
Attenuation of glucose-stimulated insulin secretion.
Species:  Rat
Tissue:  Isolated perfused pancreas.
References:  57
Enhancement of REM (rapid eye movement) sleep and wakefulness.
Species:  Rat
Tissue:  In vivo.
References:  32
Physiological Consequences of Altering Gene Expression Click here for help
Adenovirus-mediated up-regulation of rat recombinant UT expression in neonatal cardiomyocytes results in significant urotensin-II-dependent activation of hypertrophic signaling (increased total protein content).
Species:  Rat
Tissue: 
Technique:  Retroviral infection
References:  63
Selective attenuation of vasoconstrictor phenotype to urotensin-II in UT knockout mice
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  4
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Uts2rtm1Djbe Uts2rtm1Djbe/Uts2rtm1Djbe
B6.129P2-Uts2r
MGI:2183450  MP:0000250 abnormal vasoconstriction PMID: 12770952 
General Comments
In addition to human, rat and mouse UT, full-length primate UT has been cloned (389 amino acid residues, Accession number Q8HYC3) [25]. In addition, SwissProt contains an entry for a (partial) bovine UT sequence (Accession number P49220).

The detailed pharmacological characterization of many of the assays described herein is somewhat limited currently due to a lack of suitable, well characterized tools compounds. However, this is likely to change in the near future due significant advances made recently with respect to the development of peptidic and small molecule agonists and antagonists for UT (see [5,7-8,10,15,27,29,31,35-36], [16,20]).

The response of humans to systemic U-II administration is somewhat ambiguous [20-21]. Whereas Bohm & Pernow [9] reported that brachial artery infusion of U-II dose-dependently reduced forearm blood flow in normal human volunteers, Webb and colleagues [1,66] unable to observe a similar phenomenon in man using strikingly similar methodologies. Notably, Lim et al. [41] have recently compared the effect of iontophoresed U-II on skin microvascular tone in normal subjects and patients with congestive heart failure. Using laser Doppler velocimetry, this group report dose-dependent U-II mediated vasodilation in normal subjects. This contrasts with the vasoconstrictor response seen in patients with heart failure.

Recently, it has been suggested that the potential pathophysiological actions of U-II extend beyond the cardiovascular system to encompass metabolic diseases (for recent reviews see [20,28]). Indeed, a recent report Wenyi et al. [65] have proposed a role for U-II in the control of insulin sensitivity and the development of diabetes mellitus based on a pharmacogenomic study which examined the presence of a single nucleotide polymorphism in the human preproU-II gene, specifically S89N (chromosome 1p36-p32 is proposed as being linked to Type 2 diabetes in Japanese subjects).

In addition to renal epithelia (procine LLCPK1 cells [46]) and rat neurons ( dissociated spinal cord neurons [26]), native U-II binding sites/functional receptors have recently been described in two human skeletal muscle cells lines (the rhabdomyosarcoma cell lines SJRH30 and TE-671 [6,22]).

References

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1. Affolter JT, Newby DE, Wilkinson IB, Winter MJ, Balment RJ, Webb DJ. (2002) No effect on central or peripheral blood pressure of systemic urotensin II infusion in humans. Br J Clin Pharmacol, 54 (6): 617-21. [PMID:12492609]

2. Ames RS, Sarau HM, Chambers JK, Willette RN, Aiyar NV, Romanic AM, Louden CS, Foley JJ, Sauermelch CF, Coatney RW et al.. (1999) Human urotensin-II is a potent vasoconstrictor and agonist for the orphan receptor GPR14. Nature, 401 (6750): 282-6. [PMID:10499587]

3. Bandholtz S, Erdmann S, von Hacht JL, Exner S, Krause G, Kleinau G, Grötzinger C. (2016) Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist. J Med Chem, 59 (22): 10100-10112. [PMID:27791374]

4. Behm DJ, Harrison SM, Ao Z, Maniscalco K, Pickering SJ, Grau EV, Woods TN, Coatney RW, Doe CP, Willette RN et al.. (2003) Deletion of the UT receptor gene results in the selective loss of urotensin-II contractile activity in aortae isolated from UT receptor knockout mice. Br J Pharmacol, 139 (2): 464-72. [PMID:12770952]

5. Behm DJ, Herold CL, Ohlstein EH, Knight SD, Dhanak D, Douglas SA. (2002) Pharmacological characterization of SB-710411 (Cpa-c[D-Cys-Pal-D-Trp-Lys-Val-Cys]-Cpa-amide), a novel peptidic urotensin-II receptor antagonist. Br J Pharmacol, 137 (4): 449-58. [PMID:12359626]

6. Birker-Robaczewska M, Boukhadra C, Studer R, Mueller C, Binkert C, Nayler O. (2003) The expression of urotensin II receptor (U2R) is up-regulated by interferon-gamma. J Recept Signal Transduct Res, 23 (4): 289-305. [PMID:14753294]

7. Boucard AA, Sauvé SS, Guillemette G, Escher E, Leduc R. (2003) Photolabelling the rat urotensin II/GPR14 receptor identifies a ligand-binding site in the fourth transmembrane domain. Biochem J, 370 (Pt 3): 829-38. [PMID:12495432]

8. Brkovic A, Hattenberger A, Kostenis E, Klabunde T, Flohr S, Kurz M, Bourgault S, Fournier A. (2003) Functional and binding characterizations of urotensin II-related peptides in human and rat urotensin II-receptor assay. J Pharmacol Exp Ther, 306 (3): 1200-9. [PMID:12807997]

9. Böhm F, Pernow J. (2002) Urotensin II evokes potent vasoconstriction in humans in vivo. Br J Pharmacol, 135 (1): 25-7. [PMID:11786476]

10. Camarda V, Guerrini R, Kostenis E, Rizzi A, Calò G, Hattenberger A, Zucchini M, Salvadori S, Regoli D. (2002) A new ligand for the urotensin II receptor. Br J Pharmacol, 137 (3): 311-4. [PMID:12237249]

11. Chatenet D, Dubessy C, Boularan C, Scalbert E, Pfeiffer B, Renard P, Lihrmann I, Pacaud P, Tonon MC, Vaudry H et al.. (2006) Structure-activity relationships of a novel series of urotensin II analogues: identification of a urotensin II antagonist. J Med Chem, 49 (24): 7234-8. [PMID:17125276]

12. Clark SD, Nothacker HP, Blaha CD, Tyler CJ, Duangdao DM, Grupke SL, Helton DR, Leonard CS, Civelli O. (2005) Urotensin II acts as a modulator of mesopontine cholinergic neurons. Brain Res, 1059 (2): 139-48. [PMID:16183039]

13. Clozel M, Binkert C, Birker-Robaczewska M, Boukhadra C, Ding SS, Fischli W, Hess P, Mathys B, Morrison K, Müller C et al.. (2004) Pharmacology of the urotensin-II receptor antagonist palosuran (ACT-058362; 1-[2-(4-benzyl-4-hydroxy-piperidin-1-yl)-ethyl]-3-(2-methyl-quinolin-4-yl)-urea sulfate salt): first demonstration of a pathophysiological role of the urotensin System. J Pharmacol Exp Ther, 311 (1): 204-12. [PMID:15146030]

14. Coy DH, Rossowski WJ, Cheng BL, Taylor JE. (2002) Structural requirements at the N-terminus of urotensin II octapeptides. Peptides, 23 (12): 2259-64. [PMID:12535707]

15. Croston GE, Olsson R, Currier EA, Burstein ES, Weiner D, Nash N, Severance D, Allenmark SG, Thunberg L, Ma JN et al.. (2002) Discovery of the first nonpeptide agonist of the GPR14/urotensin-II receptor: 3-(4-chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954). J Med Chem, 45 (23): 4950-3. [PMID:12408704]

16. Dhanak D, Neeb MJ, Douglas SA. (2003) Urotensin-II receptor modulators. Ann Rep Med Chem, 38: 99-110.

17. Diallo M, Jarry M, Desrues L, Castel H, Chatenet D, Leprince J, Vaudry H, Tonon MC, Gandolfo P. (2008) [Orn5]URP acts as a pure antagonist of urotensinergic receptors in rat cortical astrocytes. Peptides, 29 (5): 813-9. [PMID:18082287]

18. Doan ND, Nguyen TT, Létourneau M, Turcotte K, Fournier A, Chatenet D. (2012) Biochemical and pharmacological characterization of nuclear urotensin-II binding sites in rat heart. Br J Pharmacol, 166 (1): 243-57. [PMID:22044114]

19. Douglas SA, Behm DJ, Aiyar NV, Naselsky D, Disa J, Brooks DP, Ohlstein EH, Gleason JG, Sarau HM, Foley JJ et al.. (2005) Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375. Br J Pharmacol, 145 (5): 620-35. [PMID:15852036]

20. Douglas SA, Dhanak D, Johns DG. (2004) From 'gills to pills': urotensin-II as a regulator of mammalian cardiorenal function. Trends Pharmacol Sci, 25 (2): 76-85. [PMID:15102493]

21. Douglas SA, Gupta D. (2003) Endoscopic assisted external approach anterior ethmoidal artery ligation for the management of epistaxis. J Laryngol Otol, 117 (2): 132-3. [PMID:12625888]

22. Douglas SA, Naselsky D, Ao Z, Disa J, Herold CL, Lynch F, Aiyar NV. (2004) Identification and pharmacological characterization of native, functional human urotensin-II receptors in rhabdomyosarcoma cell lines. Br J Pharmacol, 142 (6): 921-32. [PMID:15210573]

23. Douglas SA, Sulpizio AC, Piercy V, Sarau HM, Ames RS, Aiyar NV, Ohlstein EH, Willette RN. (2000) Differential vasoconstrictor activity of human urotensin-II in vascular tissue isolated from the rat, mouse, dog, pig, marmoset and cynomolgus monkey. Br J Pharmacol, 131 (7): 1262-74. [PMID:11090097]

24. Dubessy C, Cartier D, Lectez B, Bucharles C, Chartrel N, Montero-Hadjadje M, Bizet P, Chatenet D, Tostivint H, Scalbert E et al.. (2008) Characterization of urotensin II, distribution of urotensin II, urotensin II-related peptide and UT receptor mRNAs in mouse: evidence of urotensin II at the neuromuscular junction. J Neurochem, 107 (2): 361-74. [PMID:18710417]

25. Elshourbagy NA, Douglas SA, Shabon U, Harrison S, Duddy G, Sechler JL, Ao Z, Maleeff BE, Naselsky D, Disa J et al.. (2002) Molecular and pharmacological characterization of genes encoding urotensin-II peptides and their cognate G-protein-coupled receptors from the mouse and monkey. Br J Pharmacol, 136 (1): 9-22. [PMID:11976263]

26. Filipeanu CM, Brailoiu E, Le Dun S, Dun NJ. (2002) Urotensin-II regulates intracellular calcium in dissociated rat spinal cord neurons. J Neurochem, 83 (4): 879-84. [PMID:12421360]

27. Flohr S, Kurz M, Kostenis E, Brkovich A, Fournier A, Klabunde T. (2002) Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II. J Med Chem, 45 (9): 1799-805. [PMID:11960491]

28. Gilbert RE, Douglas SA, Krum H. (2004) Urotensin-II as a novel therapeutic target in the clinical management of cardiorenal disease. Curr Opin Investig Drugs, 5 (3): 276-82. [PMID:15083593]

29. Grieco P, Carotenuto A, Campiglia P, Zampelli E, Patacchini R, Maggi CA, Novellino E, Rovero P. (2002) A new, potent urotensin II receptor peptide agonist containing a Pen residue at the disulfide bridge. J Med Chem, 45 (20): 4391-4. [PMID:12238917]

30. Herold CL, Behm DJ, Buckley PT, Foley JJ, Wixted WE, Sarau HM, Douglas SA. (2003) The neuromedin B receptor antagonist, BIM-23127, is a potent antagonist at human and rat urotensin-II receptors. Br J Pharmacol, 139 (2): 203-7. [PMID:12770925]

31. Herold CL, Behm DJ, Buckley PT, FoleyJJ, null, Douglas SA. (2002) The peptidic somatostatin analogs lanreotide, BIM-23127 and BIM 23042 are urotensin-II receptor ligands. Pharmacologist, 44: 170-171.

32. Huitron-Resendiz S, Kristensen MP, Sánchez-Alavez M, Clark SD, Grupke SL, Tyler C, Suzuki C, Nothacker HP, Civelli O, Criado JR et al.. (2005) Urotensin II modulates rapid eye movement sleep through activation of brainstem cholinergic neurons. J Neurosci, 25 (23): 5465-74. [PMID:15944374]

33. Jin J, An M, Sapienza A, Aiyar N, Naselsky D, Sarau HM, Foley JJ, Salyers KL, Knight SD, Keenan RM et al.. (2008) Urotensin-II receptor antagonists: synthesis and SAR of N-cyclic azaalkyl benzamides. Bioorg Med Chem Lett, 18 (14): 3950-4. [PMID:18573659]

34. Jin J, Dhanak D, Knight SD, Widdowson K, Aiyar N, Naselsky D, Sarau HM, Foley JJ, Schmidt DB, Bennett CD et al.. (2005) Aminoalkoxybenzyl pyrrolidines as novel human urotensin-II receptor antagonists. Bioorg Med Chem Lett, 15 (13): 3229-32. [PMID:15936190]

35. Kinney WA, Almond Jr HR, Qi J, Smith CE, Santulli RJ, de Garavilla L, Andrade-Gordon P, Cho DS, Everson AM, Feinstein MA et al.. (2002) Structure-function analysis of urotensin II and its use in the construction of a ligand-receptor working model. Angew Chem Int Ed Engl, 41 (16): 2940-4. [PMID:12203418]

36. Labarrère P, Chatenet D, Leprince J, Marionneau C, Loirand G, Tonon MC, Dubessy C, Scalbert E, Pfeiffer B, Renard P et al.. (2003) Structure-activity relationships of human urotensin II and related analogues on rat aortic ring contraction. J Enzyme Inhib Med Chem, 18 (2): 77-88. [PMID:12943190]

37. Lawson EC, Luci DK, Ghosh S, Kinney WA, Reynolds CH, Qi J, Smith CE, Wang Y, Minor LK, Haertlein BJ et al.. (2009) Nonpeptide urotensin-II receptor antagonists: a new ligand class based on piperazino-phthalimide and piperazino-isoindolinone subunits. J Med Chem, 52 (23): 7432-45. [PMID:19731961]

38. Lehmann F, Currier EA, Clemons B, Hansen LK, Olsson R, Hacksell U, Luthman K. (2009) Novel and potent small-molecule urotensin II receptor agonists. Bioorg Med Chem, 17 (13): 4657-65. [PMID:19481466]

39. Lehmann F, Currier EA, Olsson R, Hacksell U, Luthman K. (2005) Isochromanone-based urotensin-II receptor agonists. Bioorg Med Chem, 13 (8): 3057-68. [PMID:15781415]

40. Lehmann F, Lake L, Currier EA, Olsson R, Hacksell U, Luthman K. (2007) Design, parallel synthesis and SAR of novel urotensin II receptor agonists. Eur J Med Chem, 42 (2): 276-85. [PMID:17112638]

41. Lim M, Honisett S, Sparkes CD, Komesaroff P, Kompa A, Krum H. (2004) Differential effect of urotensin II on vascular tone in normal subjects and patients with chronic heart failure. Circulation, 109 (10): 1212-4. [PMID:15007012]

42. Liu Q, Pong SS, Zeng Z, Zhang Q, Howard AD, Williams Jr DL, Davidoff M, Wang R, Austin CP, McDonald TP et al.. (1999) Identification of urotensin II as the endogenous ligand for the orphan G-protein-coupled receptor GPR14. Biochem Biophys Res Commun, 266 (1): 174-8. [PMID:10581185]

43. Maguire JJ, Davenport AP. (2002) Is urotensin-II the new endothelin?. Br J Pharmacol, 137: 579-588. [PMID:12381671]

44. Maguire JJ, Kuc RE, Davenport AP. (2000) Orphan-receptor ligand human urotensin II: receptor localization in human tissues and comparison of vasoconstrictor responses with endothelin-1. Br J Pharmacol, 131 (3): 441-6. [PMID:11015293]

45. Marchese A, Heiber M, Nguyen T, Heng HH, Saldivia VR, Cheng R, Murphy PM, Tsui LC, Shi X, Gregor P et al.. (1995) Cloning and chromosomal mapping of three novel genes, GPR9, GPR10, and GPR14, encoding receptors related to interleukin 8, neuropeptide Y, and somatostatin receptors. Genomics, 29 (2): 335-44. [PMID:8666380]

46. Matsushita M, Shichiri M, Fukai N, Ozawa N, Yoshimoto T, Takasu N, Hirata Y. (2003) Urotensin II is an autocrine/paracrine growth factor for the porcine renal epithelial cell line, LLCPK1. Endocrinology, 144 (5): 1825-31. [PMID:12697688]

47. Mori M, Sugo T, Abe M, Shimomura Y, Kurihara M, Kitada C, Kikuchi K, Shintani Y, Kurokawa T, Onda H et al.. (1999) Urotensin II is the endogenous ligand of a G-protein-coupled orphan receptor, SENR (GPR14). Biochem Biophys Res Commun, 265 (1): 123-9. [PMID:10548501]

48. Nishi M, Yonesu K, Tagawa H, Kato M, Marumoto S, Nagayama T. (2019) A Novel and Highly Potent Urotensin II Receptor Antagonist Inhibits Urotensin II-Induced Pressure Response in Mice. J Cardiovasc Pharmacol, 73 (1): 15-21. [PMID:30608334]

49. Nothacker HP, Wang Z, McNeill AM, Saito Y, Merten S, O'Dowd B, Duckles SP, Civelli O. (1999) Identification of the natural ligand of an orphan G-protein-coupled receptor involved in the regulation of vasoconstriction. Nat Cell Biol, 1 (6): 383-5. [PMID:10559967]

50. Ozoux ML, Briand V, Pelat M, Barbe F, Schaeffer P, Beauverger P, Poirier B, Guillon JM, Petit F, Altenburger JM et al.. (2020) Potential Therapeutic Value of Urotensin II Receptor Antagonist in Chronic Kidney Disease and Associated Comorbidities. J Pharmacol Exp Ther, 374 (1): 24-37. [PMID:32332113]

51. Patacchini R, Santicioli P, Giuliani S, Grieco P, Novellino E, Rovero P, Maggi CA. (2003) Urantide, an ultrapotent urotensin II antagonist peptide in the rat aorta. Br J Pharmacol, 140: 1155-1158. [PMID:14645137]

52. Rakowski E, Hassan GS, Dhanak D, Ohlstein EH, Douglas SA, Giaid A. (2005) A role for urotensin II in restenosis following balloon angioplasty: use of a selective UT receptor blocker. J Mol Cell Cardiol, 39 (5): 785-91. [PMID:16171813]

53. Rossowski WJ, Cheng BL, Taylor JE, Datta R, Coy DH. (2002) Human urotensin II-induced aorta ring contractions are mediated by protein kinase C, tyrosine kinases and Rho-kinase: inhibition by somatostatin receptor antagonists. Eur J Pharmacol, 438 (3): 159-70. [PMID:11909607]

54. Russell FD, Molenaar P, O'Brien DM. (2001) Cardiostimulant effects of urotensin-II in human heart in vitro. Br J Pharmacol, 132 (1): 5-9. [PMID:11156554]

55. Saetrum Opgaard O, Nothacker H, Ehlert FJ, Krause DN. (2000) Human urotensin II mediates vasoconstriction via an increase in inositol phosphates. Eur J Pharmacol, 406 (2): 265-71. [PMID:11020490]

56. Sauzeau V, Le Mellionnec E, Bertoglio J, Scalbert E, Pacaud P, Loirand G. (2001) Human urotensin II-induced contraction and arterial smooth muscle cell proliferation are mediated by RhoA and Rho-kinase. Circ Res, 88 (11): 1102-4. [PMID:11397774]

57. Silvestre RA, Rodríguez-Gallardo J, Egido EM, Marco J. (2001) Effect of leptin on insulin, glugacon and somatostatin secretion in the perfused rat pancreas. Horm Metab Res, 33 (4): 207-12. [PMID:11383923]

58. Sugo T, Mori M. (2008) Another ligand fishing for G protein-coupled receptor 14. Discovery of urotensin II-related peptide in the rat brain. Peptides, 29 (5): 809-12. [PMID:17628210]

59. Sugo T, Murakami Y, Shimomura Y, Harada M, Abe M, Ishibashi Y, Kitada C, Miyajima N, Suzuki N, Mori M et al.. (2003) Identification of urotensin II-related peptide as the urotensin II-immunoreactive molecule in the rat brain. Biochem Biophys Res Commun, 310 (3): 860-8. [PMID:14550283]

60. Tal M, Ammar DA, Karpuj M, Krizhanovsky V, Naim M, Thompson DA. (1995) A novel putative neuropeptide receptor expressed in neural tissue, including sensory epithelia. Biochem Biophys Res Commun, 209 (2): 752-9. [PMID:7733947]

61. Tamura K, Okazaki M, Tamura M, Isozumi K, Tasaki H, Nakashima Y. (2003) Urotensin II-induced activation of extracellular signal-regulated kinase in cultured vascular smooth muscle cells: involvement of cell adhesion-mediated integrin signaling. Life Sci, 72 (9): 1049-60. [PMID:12495783]

62. Tandon R, Soni A, Singh RK, Sodhi R, Seth MK, Sinha S, Sahdev S, Dhage G, Das B, Dastidar SG et al.. (2020) Identification of novel Urotensin-II receptor antagonists with potent inhibition of U-II induced pressor response in mice. Eur J Pharmacol, 886: 173391. [PMID:32745605]

63. Tzanidis A, Hannan RD, Thomas WG, Onan D, Autelitano DJ, See F, Kelly DJ, Gilbert RE, Krum H. (2003) Direct actions of urotensin II on the heart: implications for cardiac fibrosis and hypertrophy. Circ Res, 93 (3): 246-53. [PMID:12842917]

64. Watanabe T, Pakala R, Katagiri T, Benedict CR. (2001) Synergistic effect of urotensin II with mildly oxidized LDL on DNA synthesis in vascular smooth muscle cells. Circulation, 104 (1): 16-8. [PMID:11435331]

65. Wenyi Z, Suzuki S, Hirai M, Hinokio Y, Tanizawa Y, Matsutani A, Satoh J, Oka Y. (2003) Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects. Diabetologia, 46 (7): 972-6. [PMID:12830381]

66. Wilkinson IB, Affolter JT, de Haas SL, Pellegrini MP, Boyd J, Winter MJ, Balment RJ, Webb DJ. (2002) High plasma concentrations of human urotensin II do not alter local or systemic hemodynamics in man. Cardiovasc Res, 53 (2): 341-7. [PMID:11827684]

67. Ziltener P, Mueller C, Haenig B, Scherz MW, Nayler O. (2002) Urotensin II mediates ERK1/2 phosphorylation and proliferation in GPR14-transfected cell lines. J Recept Signal Transduct Res, 22 (1-4): 155-68. [PMID:12503613]

68. Zou Y, Nagai R, Yamazaki T. (2001) Urotensin II induces hypertrophic responses in cultured cardiomyocytes from neonatal rats. FEBS Lett, 508 (1): 57-60. [PMID:11707268]

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