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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

Contents:

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
Alphafold Q9UKP6 (Hs), Q8VIH9 (Mm), P49684 (Rn)
ChEMBL Target CHEMBL3764 (Hs), CHEMBL2346494 (Mm), CHEMBL4921 (Rn)
Ensembl Gene ENSG00000181408 (Hs), ENSMUSG00000039321 (Mm), ENSRNOG00000036669 (Rn)
Entrez Gene 2837 (Hs), 217369 (Mm), 57305 (Rn)
Human Protein Atlas ENSG00000181408 (Hs)
KEGG Gene hsa:2837 (Hs), mmu:217369 (Mm), rno:57305 (Rn)
OMIM 600896 (Hs)
Pharos Q9UKP6 (Hs)
RefSeq Nucleotide NM_018949 (Hs), NM_145440 (Mm), NM_020537 (Rn)
RefSeq Protein NP_061822 (Hs), NP_663415 (Mm), NP_065412 (Rn)
UniProtKB Q9UKP6 (Hs), Q8VIH9 (Mm), P49684 (Rn)
Wikipedia UTS2R (Hs)
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
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
Cardiac contractility.
Species:  Human
Tissue:  Isolated right atrial trabeculae.
References:  54
Regulation of locomotor function.
Species:  Mouse
Tissue:  In vivo.
References:  12
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]

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