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Richard Leduc - One of the best experts on this subject based on the ideXlab platform.
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Biased signaling regulates the pleiotropic effects of the urotensin II Receptor to modulate its cellular behaviors
FASEB Journal, 2014Co-Authors: Cédric Brulé, Richard Leduc, Nicolas Perzo, Jane-eileen Joubert, Xavier Sainsily, Hélène Castel, Laurent PrézeauAbstract:Biased agonism by G-protein-coupled Receptor ligands has opened up strategies for targeted physiological or therapeutic actions. We hypothesized that urotensin II (UII)-derived peptides displayed unexpected physiological effects because of such biased signaling on the UII human urotensin (hUT) Receptor. We determined the coupling to G proteins and beta-arrestins of the UII-activated hUT Receptor expressed in HEK293 using bioluminescence resonance energy transfer (BRET) biosensors, as well as the production of IP1-3 and cAMP using homogenous time-resolved Forster resonance energy transfer (FRET) (HTRF)-based assays. The activated Receptor coupled to Gi1, GoA, Gq, and G13, excluding Gs, and recruited beta-arrestins 1 and 2. Integration of these pathways led to a 2-phase kinetic phosphorylation of ERK1/2 kinases. The tested peptides induced three different profiles: UII, urotensin-related peptide (URP), and UII4-11 displayed the full profile; [Orn(8)]UII and [Orn(5)]URP activated G proteins, although with pEC50s 5-10x higher, and did not or barely recruited beta-arrestin; urantide also failed to recruit beta-arrestin but displayed a reversed rank order for Gi and Gq vs. Go pEC50s (-8.79+/-0.20, -8.43+/-0.21, and -7.86+/-0.36, respectively, for urantide, -7.87+/-0.10, -7.23+/-0.27, and -8.55+/-0.19, respectively, for [Orn(5)]URP) and was a partial agonist of all G-protein pathways. Interestingly, the peptides differently modulated cell survival but similarly induced cell migration and adhesion. Thus, we demonstrate biased signaling between beta-arrestin and G proteins, and between G-protein subtypes, which dictates the Receptor's cellular responses.
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biased signaling regulates the pleiotropic effects of the urotensin ii Receptor to modulate its cellular behaviors
The FASEB Journal, 2014Co-Authors: Cédric Brulé, Richard Leduc, Nicolas Perzo, Jane-eileen Joubert, Xavier Sainsily, Hélène Castel, Laurent PrézeauAbstract:Biased agonism by G-protein-coupled Receptor ligands has opened up strategies for targeted physiological or therapeutic actions. We hypothesized that urotensin II (UII)-derived peptides displayed unexpected physiological effects because of such biased signaling on the UII human urotensin (hUT) Receptor. We determined the coupling to G proteins and β-arrestins of the UII-activated hUT Receptor expressed in HEK293 using bioluminescence resonance energy transfer (BRET) biosensors, as well as the production of IP1-3 and cAMP using homogenous time-resolved Forster resonance energy transfer (FRET) (HTRF)-based assays. The activated Receptor coupled to Gi1, GoA, Gq, and G13, excluding Gs, and recruited β-arrestins 1 and 2. Integration of these pathways led to a 2-phase kinetic phosphorylation of ERK1/2 kinases. The tested peptides induced three different profiles: UII, urotensin-related peptide (URP), and UII4–11 displayed the full profile; [Orn8]UII and [Orn5]URP activated G proteins, although with pEC50s 5–10×...
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Identification of transmembrane domain 6 & 7 residues that contribute to the binding pocket of the urotensin II Receptor
Biochemical pharmacology, 2009Co-Authors: Brian J. Holleran, Marie-eve Beaulieu, Pierre Lavigne, Emanuel Escher, Gaétan Guillemette, Ivana Domazet, Li Ping Yan, Richard LeducAbstract:Abstract Urotensin II (U-II), a cyclic undecapeptide, is the natural ligand of the urotensin II (UT) Receptor, a G protein-coupled Receptor. In the present study, we used the substituted-cysteine accessibility method to identify specific residues in transmembrane domains (TMDs) six and seven of the rat urotensin II Receptor (rUT) that contribute to the formation of the binding pocket of the Receptor. Each residue in the R256 (6.32) -Q283 (6.59) fragment of TMD6 and the A295 (7.31) -T321 (7.57) fragment of TMD7 was mutated, individually, to a cysteine. The resulting mutants were expressed in COS-7 cells, which were subsequently treated with the positively charged methanethiosulfonate-ethylammonium (MTSEA) or the negatively charged methanethiosulfonate-ethylsulfonate (MTSES) sulfhydryl-specific alkylating agents. MTSEA treatment resulted in a significant reduction in the binding of TMD6 mutants F268C (6.44) and W278C (6.54) and TMD7 mutants L298C (7.34) , T302C (7.38) , and T303C (7.39) to 125 I-U-II. MTSES treatment resulted in a significant reduction in the binding of two additional mutants, namely L282C (6.58) in TMD6 and Y300C (7.36) in TMD7. These results suggest that specific residues orient themselves within the water-accessible binding pocket of the rUT Receptor. This approach, which allowed us to identify key determinants in TMD6 and TMD7 that contribute to the UT Receptor binding pocket, enabled us to further refine our homology-based model of how U-II interacts with its cognate Receptor.
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Mutational analysis of the conserved Asp2.50 and ERY motif reveals signaling bias of the urotensin II Receptor.
Molecular pharmacology, 2008Co-Authors: Christophe D. Proulx, Brian J. Holleran, Emanuel Escher, Gaétan Guillemette, Antony A. Boucard, Richard LeducAbstract:Class A (rhodopsin-like) G protein-coupled Receptors possess conserved residues and motifs that are important for their specific activity. In the present study, we examined the role of residue Asp972.50 as well as residues Glu1473.49, Arg1483.50, and Tyr1493.51 of the ERY motif on the functionality of the urotensin II Receptor (UT). Mutations D972.50A, R1483.50A, and R1483.50H abolished the ability of UT to activate phospholipase C, whereas mutations E1473.49A and Y1493.51A reduced the ability to activate PLC by 50%. None of the mutants exhibited constitutive activity. However, R1483.50A and R1483.50H promoted ERK1/2 activation, which was abolished by 4-(3-chloroanilino)-6,7-dimethoxyquinazoline (AG1478), an inhibitor of epidermal growth factor Receptor (EGFR) tyrosine kinase activity. Both these mutants were capable of directly activating EGFR, which confirmed that they activated the mitogen-activated protein kinase (MAPK) pathway by a Gαq/11-independent transactivation of EGFR. The D972.50A, R1483.50A, and R1483.50H mutants did not readily internalize and did not promote translocation or colocalize with β-arrestin2-GFP. Finally, the agonist-induced internalization of the E1473.49A mutant Receptor was significantly increased compared with wild-type Receptor. This study highlights the major contribution of the conserved Asp2.50 residue to the functionality of the UT Receptor. The Arg residue in the ERY motif of UT is an important structural element in signaling crossroads that determine whether Gαq/11-dependent and -independent events can occur.
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Biological properties and functional determinants of the urotensin II Receptor
Peptides, 2007Co-Authors: Christophe D. Proulx, Brian J. Holleran, Pierre Lavigne, Emanuel Escher, Gaétan Guillemette, Richard LeducAbstract:The urotensin II Receptor (UT) is a member of the G protein-coupled Receptor (GPCR) family and binds the cyclic undecapeptide urotensin II (U-II) as well as the octapeptide urotensin II-related peptide (URP). The active UT mediates pleiotropic effects through various signal transduction pathways, including coupling to G proteins and activating the mitogen-activated protein kinase pathway. Several highly conserved residues and motifs of class A GPCRs that are important for activity are found in UT. This review highlights some of the putative roles of these motifs in the binding, activation and desensitization of UT.
David Chatenet - One of the best experts on this subject based on the ideXlab platform.
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New directions for urotensin II Receptor ligands
Peptide Science, 2018Co-Authors: Etienne Billard, Hassan Nassour, Mustapha Iddir, Laura Lee-gosselin, Mathilde Poujol De Molliens, David ChatenetAbstract:The urotensinergic system, formed by a G protein‐coupled Receptor (GPCR) termed UT and two endogenous peptide ligands Urotensin II (UII, H‐Glu‐Thr‐Pro‐Asp‐[Cys‐Phe‐Trp‐Lys‐Tyr‐Cys]‐Val‐OH) and Urotensin II‐related peptide (URP, H‐Ala‐[Cys‐Phe‐Trp‐Lys‐Tyr‐Cys]‐Val‐OH), is currently regarded as a potential key contributor to cardiovascular functions. While multiple animal studies have shown the therapeutic potential of UT ligands for the treatment of heart failure and atherosclerosis, their lack of efficacy in clinical studies points toward a greater understanding of UT pharmacology at both the molecular and cellular levels. UII and URP are cyclic peptides that share a common and strictly conserved bioactive cyclic core (‐Cys‐Phe‐Trp‐Lys‐Tyr‐Cys‐) but differ by their extracyclic N‐terminal residues. While sharing common biological activity, these two endogenous ligands appear to be functionally selective, displaying different specific effects through the selection/stabilization of particular UT active conformations. Thus, UII and URP should be regarded as two distinct actors in the control of cardiovascular functions. In this regard, more focus on URP biological effects had to be paid, while systematic evaluation of new antagonists against both endogenous ligands appears mandatory. Overall, this review offers an overview of the actual horizon of UT pharmacology, notably concerning the development of biased ligands and allosteric modulators.
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
Journal of Medicinal Chemistry, 2017Co-Authors: Antoine Douchez, David Chatenet, Etienne Billard, Terence Hébert, William LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II Receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system.
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
Journal of medicinal chemistry, 2017Co-Authors: Antoine Douchez, David Chatenet, Etienne Billard, Terence E. Hébert, William D. LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II Receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Eff...
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
2017Co-Authors: Antoine Douchez, David Chatenet, Etienne Billard, Terence E. Hébert, William D. LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II Receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system
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Urotensin II((4-11)) Azasulfuryl Peptides: Synthesis and Biological Activity.
Journal of Medicinal Chemistry, 2016Co-Authors: Francesco Merlino, David Chatenet, Etienne Billard, Paolo Grieco, Julien Dufour-gallant, Ali M Yousif, Stéphane Turcotte, William D. LubellAbstract:Cyclic azasulfuryl (As) peptide analogs of the urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4-11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp(7) and Lys(8) residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII((4-11)) analogs 6-11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6-11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the urotensin II Receptor (UT) without agonistic activity, azasulfuryl-UII((4-11)) derivatives 7-9 reduced up to 50% of the effects of UII and urotensin II-related peptide (URP) without affecting their potency.
William D. Lubell - One of the best experts on this subject based on the ideXlab platform.
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
Journal of medicinal chemistry, 2017Co-Authors: Antoine Douchez, David Chatenet, Etienne Billard, Terence E. Hébert, William D. LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II Receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Eff...
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Design, Synthesis, and Biological Assessment of Biased Allosteric Modulation of the Urotensin II Receptor Using Achiral 1,3,4-Benzotriazepin-2-one Turn Mimics
2017Co-Authors: Antoine Douchez, David Chatenet, Etienne Billard, Terence E. Hébert, William D. LubellAbstract:Benzotriazepin-2-ones were designed to mimic the suggested bioactive γ-turn conformation of the Bip-Lys-Tyr tripeptide in Urocontrin ([Bip4]URP), which modulates the urotensin II Receptor (UT) and differentiates the effects of the endogenous ligands urotensin II (UII) and urotensin II-related peptide (URP). Twenty-six benzotriazepin-2-ones were synthesized by acylation of anthranilate-derived amino ketones with an aza-glycine equivalent, chemoselective nitrogen functionalization, and ring closure. Several mimics exhibited selective modulatory effects on hUII- and URP-associated vasoconstriction in an ex vivo rat aortic ring bioassay. The C5 p-hydroxyphenethenyl benzotriazepin-2-one 20g decreased hUII potency and efficacy without changing URP induced vasoconstriction. Its saturated phenethyl counterpart 23g decreased URP potency without influencing hUII-mediated contraction. To our knowledge, 20g and 23g represent the first achiral molecules that modulate selectively hUII and URP biological activities. Effectively synthesized, benzotriaepin-2-one turn mimics offer the potential to differentiate the respective roles, signaling pathways, and phenotypic outcomes of hUII and URP in the UT system
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Urotensin II((4-11)) Azasulfuryl Peptides: Synthesis and Biological Activity.
Journal of Medicinal Chemistry, 2016Co-Authors: Francesco Merlino, David Chatenet, Etienne Billard, Paolo Grieco, Julien Dufour-gallant, Ali M Yousif, Stéphane Turcotte, William D. LubellAbstract:Cyclic azasulfuryl (As) peptide analogs of the urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4-11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp(7) and Lys(8) residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII((4-11)) analogs 6-11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6-11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the urotensin II Receptor (UT) without agonistic activity, azasulfuryl-UII((4-11)) derivatives 7-9 reduced up to 50% of the effects of UII and urotensin II-related peptide (URP) without affecting their potency.
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Urotensin II(4–11) Azasulfuryl Peptides: Synthesis and Biological Activity
2016Co-Authors: Francesco Merlino, David Chatenet, Paolo Grieco, Julien Dufour-gallant, Ali M Yousif, Étienne Billard, Stéphane Turcotte, William D. LubellAbstract:Cyclic azasulfuryl (As) peptide analogs of the urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4–11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp7 and Lys8 residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII(4–11) analogs 6–11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6–11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the urotensin II Receptor (UT) without agonistic activity, azasulfuryl-UII(4–11) derivatives 7–9 reduced up to 50% of the effects of UII and urotensin II-related peptide (URP) without affecting their potency
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De Novo Conception of Small Molecule Modulators Based on Endogenous Peptide Ligands: Pyrrolodiazepin-2-one γ-Turn Mimics That Differentially Modulate Urotensin II Receptor-Mediated Vasoconstriction ex Vivo.
Journal of Medicinal Chemistry, 2015Co-Authors: Julien Dufour-gallant, David Chatenet, William D. LubellAbstract:A proof-of-concept library of pyrrolodiazepinone small molecules was designed based on the Bip-Lys-Tyr motif found in a recently described modulator of the urotensinergic system. Solid-phase synthesis provided 13 analogues, which were tested for their ability to modulate selectively and differentially the potency (EC50) and efficacy (E(max)) of hUII and URP ex vivo in a rat aortic ring bioassay. Notably, at 14 μM, pyrrolodiazepinone R-4a inhibited completely hUII-induced contractions and increased URP-associated vasoconstriction. Pyrrolodiazepinone R-4a represents, to the best of our knowledge, a first-in-class small molecule that exerts a probe-dependent effect on hUII and URP biological activities and proves that UT modulators of the urotensin II Receptor (UT) can be rationally designed. The importance of the UT system in the pathogenesis and progression of cardiovascular diseases highlights the utility of pyrrolodiazepinones such as R-4a, which exhibit promising potential as tools for differentiating the respective roles, signaling pathways, and phenotypic outcomes of UII and URP in the UT system.
James J. Foley - One of the best experts on this subject based on the ideXlab platform.
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Urotensin-II Receptor antagonists: synthesis and SAR of N-cyclic azaalkyl benzamides.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Jian Jin, Steven D. Knight, Nambi Aiyar, Diane Naselsky, Henry M. Sarau, James J. Foley, Anthony Sapienza, Kevin L. Salyers, Richard M. KeenanAbstract:SAR exploration of the central diamine, benzyl, and terminal aminoalkoxy regions of the N-cyclic azaalkyl benzamide series led to the identification of very potent human Urotensin-II Receptor antagonists such as 1a with a K(i) of 4 nM. The synthesis and structure-activity relationships (SAR) of N-cyclic azaalkyl benzamides are described.
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The peptidic Urotensin-II Receptor ligand GSK248451 possesses less intrinsic activity than the low-efficacy partial agonists SB-710411 and urantide in native mammalian tissues and recombinant cell systems
British journal of pharmacology, 2006Co-Authors: David J. Behm, Henry M. Sarau, James J. Foley, Dulcie B. Schmidt, Gerald Stankus, Christopher P. Doe, Robert N. Willette, Parvathi Nuthulaganti, James A. Fornwald, Robert S. AmesAbstract:Several peptidic Urotensin-II (UT) Receptor antagonists exert 'paradoxical' agonist activity in recombinant cell- and tissue-based bioassay systems, likely the result of differential Urotensin-II Receptor (UT Receptor) signal transduction/coupling efficiency between assays. The present study has examined this phenomenon in mammalian arteries and recombinant UT-HEK (human embryonic kidney) cells.BacMam-mediated recombinant UT Receptor upregulation in HEK cells augmented agonist activity for all four peptidic UT ligands studied. The nominal rank order of relative intrinsic efficacy was U-II>urantide ([Pen(5)-DTrp(7)-Orn(8)]hU-II(4-11))>SB-710411 (Cpa-c[DCys-Pal-DTrp-Lys-Val-Cys]-Cpa-amide)>>GSK248451 (Cin-c[DCys-Pal-DTrp-Orn-Val-Cys]-His-amide) (the relative coupling efficiency of recombinant HEK cells was cat>human>>rat UT Receptor). The present study further demonstrated that the use of high signal transduction/coupling efficiency isolated blood vessel assays (primate>cat arteries) is required in order to characterize UT Receptor antagonism thoroughly. This cannot be attained simply by using the rat isolated aorta, an artery with low signal transduction/coupling efficiency in which low-efficacy agonists appear to function as antagonists. In contrast to the 'low-efficacy agonists' urantide and SB-710411, GSK248451 functioned as a potent UT Receptor antagonist in all native isolated tissues studied (UT Receptor selectivity was confirmed in the rat aorta). Further, GSK248451 exhibited an extremely low level of relative intrinsic activity in recombinant HEK cells (4-5-fold less than seen with urantide). Since GSK248451 (1 mg kg(-1), i.v.) blocked the systemic pressor actions of exogenous U-II in the anaesthetized cat, it represents a suitable peptidic tool antagonist for delineating the role of U-II in the aetiology of mammalian cardiometabolic diseases.
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Aminoalkoxybenzyl pyrrolidines as novel human Urotensin-II Receptor antagonists
Bioorganic & medicinal chemistry letters, 2005Co-Authors: Jian Jin, Dashyant Dhanak, Steven D. Knight, Widdowson Katherine L, Nambi Aiyar, Diane Naselsky, Henry M. Sarau, James J. Foley, Dulcie B. Schmidt, Carl D. BennettAbstract:Abstract High throughput screening of the corporate compound collection led to the discovery of a novel series of substituted aminoalkoxybenzyl pyrrolidines as human Urotensin-II Receptor antagonists. The synthesis, initial structure–activity relationships, and optimization of the initial hit that led to the identification of a truncated sub-series, represented by SB-436811 ( 1a ), are described.
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nonpeptidic urotensin ii Receptor antagonists i in vitro pharmacological characterization of sb 706375
British Journal of Pharmacology, 2005Co-Authors: Stephen A. Douglas, David J. Behm, Jyoti Disa, Nambi Aiyar, Diane Naselsky, Henry M. Sarau, David P Brooks, Eliot H Ohlstein, John G Gleason, James J. FoleyAbstract:1 SB-706375 potently inhibited [125I]hU-II binding to both mammalian recombinant and ‘native’ UT Receptors (Ki 4.7±1.5 to 20.7±3.6 nM at rodent, feline and primate recombinant UT Receptors and Ki 5.4±0.4 nM at the endogenous UT Receptor in SJRH30 cells). 2 Prior exposure to SB-706375 (1 μM, 30 min) did not alter [125I]hU-II binding affinity or density in recombinant cells (KD 3.1±0.4 vs 5.8±0.9 nM and Bmax 3.1±1.0 vs 2.8±0.8 pmol mg−1) consistent with a reversible mode of action. 3 The novel, nonpeptidic radioligand [3H]SB-657510, a close analogue of SB-706375, bound to the monkey UT Receptor (KD 2.6±0.4 nM, Bmax 0.86±0.12 pmol mg−1) in a manner that was inhibited by both U-II isopeptides and SB-706375 (Ki 4.6±1.4 to 17.6±5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT Receptor binding domain. 4 SB-706375 was a potent, competitive hU-II antagonist across species with pKb 7.29–8.00 in HEK293-UT Receptor cells (inhibition of [Ca2+]i-mobilization) and pKb 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (Kapp∼20 nM). 5 SB-706375 was a selective U-II antagonist with 100-fold selectivity for the human UT Receptor compared to 86 distinct Receptors, ion channels, enzymes, transporters and nuclear hormones (Ki/IC50>1 μM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 μM). 6 In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT Receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals. British Journal of Pharmacology (2005) 145, 620–635. doi:10.1038/sj.bjp.0706229
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Cloning and pharmacological characterization of the cat Urotensin-II Receptor (UT).
Biochemical pharmacology, 2005Co-Authors: Nambi Aiyar, David J. Behm, Jyoti Disa, Henry M. Sarau, James J. Foley, Douglas G. Johns, Peter T. Buckley, Harjeet K. Van-der-keyl, Nabil ElshourbagyAbstract:Abstract Urotensin-II (U-II), acting through its G-protein-coupled Receptor, UT, is a possible contributor to hypertension. Variable functional responses to U-II, both within and between species studied to date, complicate the characterization of UT antagonists. In the cat, however, U-II causes systemic hypertension and constricts arterial segments isolated from several vascular beds. The purpose of this study was to clone and pharmacologically characterize cat recombinant UT to determine whether this system represents a model for characterizing UT antagonists. Cloned cat UT displayed 74% identity to primate UT, and 77% identity to rodent UT. [ 125 I] hU-II bound in a saturable manner to a single site on recombinant cat UT with high affinity ( K D 288 ± 13 pM) and high density ( B max 747 ± 66 fmol/mg protein). U-II isopeptides displayed equipotent, high affinity binding to cat UT ( K i 1.8–5.3 nM). Cat UT was coupled to intracellular [Ca 2+ ] release (EC 50 0.6 ± 0.2 nM) and total inositol phosphate (IP) formation (EC 50 0.4 ± 0.1 nM). Protein kinase C activation desensitized cat, but not human, UT-mediated IP formation. UT mRNA expression was detected in cat blood vessels, trachea, lung, and kidney, where the medulla ( K D 815 ± 34) and cortex and ( K D 316 ± 39 pM) displayed high affinity binding for human U-II (hU-II). The cat Urotensin-II Receptor represents a suitable in vitro model to examine the role of the U-II/UT system in the etiology of hypertension, assisting in the evaluation of the UT antagonists to help treat cardiovascular disease.
Stephen A. Douglas - One of the best experts on this subject based on the ideXlab platform.
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N-alkyl-5H-pyrido[4,3-b]indol-1-amines and derivatives as novel Urotensin-II Receptor antagonists.
Bioorganic & medicinal chemistry letters, 2008Co-Authors: Yonghui Wang, Brian F. Guida, Sarah K. Lawrence, Michael J. Neeb, Ralph A. Rivero, Stephen A. Douglas, Jian JinAbstract:High throughput screening of our compound collection led to the discovery of a novel series of N-alkyl-5H-pyrido[4,3-b]indol-1-amines as Urotensin-II Receptor antagonists. Synthesis, initial structure and activity relationships, functional and animal ortholog activities of the series are described.
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Non-peptidic Urotensin-II Receptor modulators
Expert Opinion on Therapeutic Patents, 2006Co-Authors: Jian Jin, Stephen A. DouglasAbstract:Urotensin-II (U-II), first isolated as a fish neuropeptide, is the most potent vasoconstrictor known to date. Through the interaction with its cognate 7-transmembrane Receptor UT (formerly known as the orphan Receptor GPR14), U-II has demonstrated potent vasoconstrictor activity in mammalian tissues including those from rats, monkeys and, most importantly, humans. Systemic administration of human U-II (hU-II) in monkey, cat and human induced profound cardiohaemodynamic effects. The U-II/UT system is purported to be involved in the (dys)regulation of cardiorenal and metabolic function and hU-II has been implicated in the aetiology of numerous diseases including hypertension, heart failure, atherosclerosis, renal failure, cirrhosis and diabetes. The impressive in vitro and in vivo pharmacological activity of U-II has stimulated a great deal of interest in identifying, designing and developing non-peptidic small molecule UT modulators. Significant advances have been made in this young but rapidly emerging re...
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nonpeptidic urotensin ii Receptor antagonists i in vitro pharmacological characterization of sb 706375
British Journal of Pharmacology, 2005Co-Authors: Stephen A. Douglas, David J. Behm, Jyoti Disa, Nambi Aiyar, Diane Naselsky, Henry M. Sarau, David P Brooks, Eliot H Ohlstein, John G Gleason, James J. FoleyAbstract:1 SB-706375 potently inhibited [125I]hU-II binding to both mammalian recombinant and ‘native’ UT Receptors (Ki 4.7±1.5 to 20.7±3.6 nM at rodent, feline and primate recombinant UT Receptors and Ki 5.4±0.4 nM at the endogenous UT Receptor in SJRH30 cells). 2 Prior exposure to SB-706375 (1 μM, 30 min) did not alter [125I]hU-II binding affinity or density in recombinant cells (KD 3.1±0.4 vs 5.8±0.9 nM and Bmax 3.1±1.0 vs 2.8±0.8 pmol mg−1) consistent with a reversible mode of action. 3 The novel, nonpeptidic radioligand [3H]SB-657510, a close analogue of SB-706375, bound to the monkey UT Receptor (KD 2.6±0.4 nM, Bmax 0.86±0.12 pmol mg−1) in a manner that was inhibited by both U-II isopeptides and SB-706375 (Ki 4.6±1.4 to 17.6±5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT Receptor binding domain. 4 SB-706375 was a potent, competitive hU-II antagonist across species with pKb 7.29–8.00 in HEK293-UT Receptor cells (inhibition of [Ca2+]i-mobilization) and pKb 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (Kapp∼20 nM). 5 SB-706375 was a selective U-II antagonist with 100-fold selectivity for the human UT Receptor compared to 86 distinct Receptors, ion channels, enzymes, transporters and nuclear hormones (Ki/IC50>1 μM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 μM). 6 In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT Receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals. British Journal of Pharmacology (2005) 145, 620–635. doi:10.1038/sj.bjp.0706229
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Inhibitory effects of putative peptidic Urotensin-II Receptor antagonists on Urotensin-II-induced contraction of cat isolated respiratory smooth muscle.
European journal of pharmacology, 2005Co-Authors: David J. Behm, Nambi Aiyar, Douglas G. Johns, Valeria Camarda, Stephen A. DouglasAbstract:Abstract Urotensin-II is purported to influence pulmonary function by modulating smooth muscle tone/growth. In the present study, Northern blot and reverse transcription polymerase chain reaction (RT-PCR) analysis indicated the presence of UT Receptor mRNA in cat trachea, bronchi and lung parenchyma. Urotensin-II contracted cat isolated trachea and bronchi with similar potencies (pEC 50 s 8.61 ± 0.07–8.81 ± 0.10). Contractile efficacies ranged from 19 ± 9% to 63 ± 11% KCl in the primary and secondary bronchi. The peptidic UT Receptor antagonists BIM-23127, SB-710411 and GSK248451 (7.18 ± 0.12, 7.52 ± 0.08 and 9.05 ± 0.16 cat recombinant UT pK i s) inhibited Urotensin-II-induced contraction of cat isolated trachea with pK b s 6.36 ± 0.11, 6.74 ± 0.07 and 9.27 ± 0.12, respectively. As such, feline lung contains significant amounts of UT mRNA and this Receptor appears to be functionally coupled to bronchoconstriction (the peptidic tool compound GSK248451 representing a sub-nanomolar inhibitor of such effects). These findings suggest that the cat represents a suitable species for future studies designed to assess the effects of the Urotensin-II Receptor on pulmonary (patho)physiology.
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Nonpeptidic urotensin‐II Receptor antagonists I: in vitro pharmacological characterization of SB‐706375
British journal of pharmacology, 2005Co-Authors: Stephen A. Douglas, David J. Behm, Jyoti Disa, Nambi Aiyar, Diane Naselsky, Henry M. Sarau, David P Brooks, Eliot H Ohlstein, John G Gleason, James J. FoleyAbstract:1 SB-706375 potently inhibited [125I]hU-II binding to both mammalian recombinant and ‘native’ UT Receptors (Ki 4.7±1.5 to 20.7±3.6 nM at rodent, feline and primate recombinant UT Receptors and Ki 5.4±0.4 nM at the endogenous UT Receptor in SJRH30 cells). 2 Prior exposure to SB-706375 (1 μM, 30 min) did not alter [125I]hU-II binding affinity or density in recombinant cells (KD 3.1±0.4 vs 5.8±0.9 nM and Bmax 3.1±1.0 vs 2.8±0.8 pmol mg−1) consistent with a reversible mode of action. 3 The novel, nonpeptidic radioligand [3H]SB-657510, a close analogue of SB-706375, bound to the monkey UT Receptor (KD 2.6±0.4 nM, Bmax 0.86±0.12 pmol mg−1) in a manner that was inhibited by both U-II isopeptides and SB-706375 (Ki 4.6±1.4 to 17.6±5.4 nM) consistent with the sulphonamides and native U-II ligands sharing a common UT Receptor binding domain. 4 SB-706375 was a potent, competitive hU-II antagonist across species with pKb 7.29–8.00 in HEK293-UT Receptor cells (inhibition of [Ca2+]i-mobilization) and pKb 7.47 in rat isolated aorta (inhibition of contraction). SB-706375 also reversed tone established in the rat aorta by prior exposure to hU-II (Kapp∼20 nM). 5 SB-706375 was a selective U-II antagonist with 100-fold selectivity for the human UT Receptor compared to 86 distinct Receptors, ion channels, enzymes, transporters and nuclear hormones (Ki/IC50>1 μM). Accordingly, the contractile responses induced in isolated aortae by KCl, phenylephrine, angiotensin II and endothelin-1 were unaltered by SB-706375 (1 μM). 6 In summary, SB-706375 is a high-affinity, surmountable, reversible and selective nonpeptide UT Receptor antagonist with cross-species activity that will assist in delineating the pathophysiological actions of U-II in mammals. British Journal of Pharmacology (2005) 145, 620–635. doi:10.1038/sj.bjp.0706229