Endothelin receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Endothelin Receptors [25]) are activated by the endogenous 21 amino-acid peptides endothelins 1-3 (endothelin-1, endothelin-2 and endothelin-3).

The renin-angiotensin system plays a key role in the regulation of blood pressure, fluid and electrolyte balance, and blood volume. In the initial step of the biochemical cascade, the proteolytic enzyme renin catalyzes the breakdown of the high-molecular-weight peptide, angiotensinogen, to angiotensin I. The report of the benzylimidazole 1 sparked our interest in the application of an overlay hypothesis strategy to aid in the design of nonpeptide angiotensin II antagonists. Careful examination of existing AII peptide structure-activity relationship helped refine our overlay hypothesis strategy and focus our synthetic efforts. Thus, a Tyr-Phe overlay hypothesis became the focus of our molecular modeling efforts. According to this overlay hypothesis, the small molecule covered the Tyr aromatic ring, Ile sidechain, and the Phe carboxylate of AII but failed to reach other regions of the octapeptide known to be important for affinity, such as the Arg and His sidechains and Phe aromatic ring.

Urotensin II (UII) is a cyclic neuropeptide that was first isolated from the urophysis of teleost fish on the basis of its ability to contract the hindgut. Subsequently, UII was characterized in tetrapods including humans. Phylogenetic studies and synteny analysis indicate that UII and its paralogous peptide urotensin II-related peptide (URP) belong to the somatostatin/cortistatin superfamily. In mammals, the UII and URP genes are primarily expressed in cholinergic neurons of the brainstem and spinal cord. UII and URP mRNAs are also present in various organs notably in the cardiovascular, renal, and endocrine systems. UII and URP activate a common G protein-coupled receptor, called UT, that exhibits relatively high sequence identity with somatostatin, opioid, and galanin receptors. The UT gene is widely expressed in the central nervous system (CNS) and in peripheral tissues including the retina, heart, vascular bed, lung, kidney, adrenal medulla, and skeletal muscle. Structure-activity relationship studies and NMR conformational analysis have led to the rational design of a number of peptidic and nonpeptidic UT agonists and antagonists. Consistent with the wide distribution of UT, UII has now been shown to exert a large array of biologic activities, in particular in the CNS, the cardiovascular system, and the kidney. Here, we review the current knowledge concerning the pleiotropic actions of UII and discusses the possible use of antagonists for future therapeutic applications.

You have accessJournal of UrologyBladder and Urethra: Anatomy, Physiology and Pharmacology (I)1 Apr 2013283 EFFECTS OF COMBINING ANTIMUSCARINICS AND Β3-ADRENOCEPTOR AGONISTS ON CONTRACTIONS INDUCED BY ELECTRICAL FIELD STIMULATION OF RAT ISOLATED URINARY BLADDER STRIPS Moèz Rekik, Céline Rouget, Stefano Palea, Philippe Lluel, Eliot H. Ohlstein, and Timothy D. Westfall Moèz RekikMoèz Rekik Toulouse, France More articles by this author , Céline RougetCéline Rouget Toulouse, France More articles by this author , Stefano PaleaStefano Palea Toulouse, France More articles by this author , Philippe LluelPhilippe Lluel Toulouse, France More articles by this author , Eliot H. OhlsteinEliot H. Ohlstein Malvern, PA More articles by this author , and Timothy D. WestfallTimothy D. Westfall Gladwyne, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1667AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES The objective of the study was to determine if combining antimuscarinics and β3-adrenoceptor agonists results in enhanced efficacy and/or potency in rat isolated urinary bladder. METHODS Rat bladder strips were cleaned of connective tissue, connected to isometric tension transducers and immersed in 5 ml organ baths with oxygenated Krebs solution containing 1 μM prazosin (to block α1-adrenoceptors). Electrical field stimulation (EFS) of bladder strips was conducted using the following parameters: maximal current 800 mA, frequency of 15 Hz, square pulse of 0.1 ms, trains of 4 s every 2 min. ICI118,551 (30 nM) was added in order to block β2-adrenoceptors. In preliminary experiments concentration response curves (CRCs) to oxybutynin, tolterodine or solifenacin were performed. In subsequent experiments, 10 nM of each antimuscarinic (or vehicle) was added followed by a CRC to solabegron, CL-316,243 or mirabegron. Contractile responses were calculated as % inhibition from basal (mean ± sem). RESULTS Phasic contractions of urinary bladder strips were inhibited in a concentration-dependent manner by both the antimuscarinics and β3-adrenoceptor agonists. The efficacy of solabegron was significantly increased in the presence of 10 nM oxybutynin, tolterodine and solifenacin, (Emax values were 63.0 ± 2.7%, 67.1 ± 2.6% and 60.6 ± 2.1%, respectively) compared to vehicle (Emax value of 48.3 ± 3.3%). The potency of solabegron was also significantly increased in the presence of both oxybutynin and tolterodine with IC50 values of 0.05 μM and 0.03 μM, respectively, versus vehicle (0.14 μM). The efficacy of CL-316,243 was also significantly increased in the presence of oxybutynin and tolterodine, (Emax values of 84.7 ± 2.7% and 91.3 ± 1.5%, respectively) compared to vehicle (Emax = 68.6 ± 3.0%). However, the potency of CL-316,243 was only significantly affected in the presence of oxybutynin (IC50 value of 1.91 nM compared with 7.36 nM for vehicle). In the presence of oxybutynin, tolterodine or solifenacin, the potency of mirabegron was significantly increased with IC50 values of 0.87 μM, 0.33 μM and 0.77 μM, respectively versus vehicle (1.71 μM), while no significant effects on efficacy were observed. CONCLUSIONS The current results demonstrate that the combination of antimuscarinics and β3-adrenoceptor agonists can result in increased efficacy and potency and supports the hypothesis that combining these compound classes in the clinic could have beneficial effects in treating urinary bladder dysfunction. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e115-e116 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Moèz Rekik Toulouse, France More articles by this author Céline Rouget Toulouse, France More articles by this author Stefano Palea Toulouse, France More articles by this author Philippe Lluel Toulouse, France More articles by this author Eliot H. Ohlstein Malvern, PA More articles by this author Timothy D. Westfall Gladwyne, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

You have accessJournal of UrologyUrodynamics/Incontinence/Female Urology: Incontinence - Evaluation & Therapy I1 Apr 2012520 THE BETA-3 ADRENOCEPTOR AGONIST SOLABEGRON IS EFFECTIVE AND SAFE FOR IMPROVING SYMPTOMS OF OVERACTIVE BLADDER Martin Michel, Alexander Von Keitz, and Eliot Ohlstein Martin MichelMartin Michel Amsterdam, Netherlands More articles by this author , Alexander Von KeitzAlexander Von Keitz Marburg, Germany More articles by this author , and Eliot OhlsteinEliot Ohlstein Malvern, PA More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.592AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Solabegron, a novel beta-3 adrenoceptor agonist with high affinity and selectivity, is in clinical development for the treatment of patients with overactive bladder. A phase II multi-center, randomized, double-blind, placebo-controlled, parallel group study was performed to evaluate the safety and efficacy of oral solabegron in women with over active bladder symptoms. METHODS 258 women were enrolled to receive solabegron 50 mg, 125 mg, or matching placebo twice daily for 8 weeks. Based on a 3-day electronic diary, patients with > 8 micturitions/24 hr, and >1 incontinence episodes/24 hr and > 1 urgency episodes/24 hr were randomized to double-blind treatment. Percent change from baseline to 8 weeks in the number of incontinence episodes/24 hr was the primary endpoint. RESULTS In this patient population the mean baseline for incontinence episodes was 4.5 episodes/24hr. For the primary endpoint, solabegron (125 mg) produced a statistical significant 65% adjusted mean reduction from baseline in incontinence episodes and an adjusted mean difference from placebo of 21% (p=0.025). The median reduction in incontinence episodes was 75% from baseline. Solabegron produced an adjusted mean reduction from placebo in incontinence episodes for both the 50 mg (23%; p=0.03) and 125 mg (32%; p=0.003) treatment groups after 4 weeks of treatment. At the 125 mg dose there was a significant reduction in the number of micturitions at week 4 (−0.7; p=0.05) and week 8 (−0.8; p=0.036). There was a marked and significant increase in the volume voided per micturition at week 8 for the solabegron 125mg treatment group (+27%; p<0.001). The extent of the solabegron response was similar in patients with or without the Trp64Arg polymorphism of the beta-3 adrenoceptor. Solabegron was safe and well-tolerated. There were no significant differences in AEs between placebo and the solabegron treatment groups. The most common AE's across the placebo and treatment groups were headache (8%, 8%), nasopharingitis (11%, 6%) and dry mouth (4%, 1%), respectively. There were no significant changes in clinical chemistry, hematology or ECG parameters. Urinary retention was not observed. There were no significant treatment differences for mean changes in ambulatory SBP, DBP, MAP or heart rate during 24 hr measurement. CONCLUSIONS The results of this phase 2 clinical study demonstrate that solabegron is efficacious, safe and well-tolerated in the treatment of patients with OAB. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e213-e214 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Martin Michel Amsterdam, Netherlands More articles by this author Alexander Von Keitz Marburg, Germany More articles by this author Eliot Ohlstein Malvern, PA More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Urotensin II (UII) and its receptor UT are upregulated in the pathological setting of various cardiovascular diseases including atherosclerosis. However, their exact role in atherosclerosis remains to be determined. In the present study we used four strains of mice; wild-type (WT), UT+ (a transgenic strain expressing human UT driven by the α-smooth muscle-specific, SM22, promoter), ApoE knockout (ko), and UT+/ApoE ko. All animals were fed high fat diet for 12 weeks. Western blot analysis revealed a significant increase in aortic UT expression in UT+ relative to WT mice (P<0.05). Aortas of ApoE ko mice expressed comparable UT protein level to that of UT+. Immunohistochemistry revealed the presence of strong expression of UT and UII proteins in the atheroma of UT+, ApoE ko and UT+/ApoE ko mice, particularly in foam cells. Serum cholesterol and triglyceride levels were significantly increased in ApoE ko and in UT+/ApoE ko but not in UT+ mice when compared to WT mice (P<0.0001). Analysis of aortas showed a significant increase in atherosclerotic lesion in the UT+, ApoE ko and UT+/ApoE ko compared to WT mice (P<0.05). Oral administration of the UT receptor antagonist SB-657510A (30μg/Kg/day gavage) for 10 weeks in a group of ApoE ko mice fed on high fat diet resulted in a significant reduction of lesion (P<0.001). SB-657510A also significantly reduced ACAT-1 protein expression in the atherosclerotic lesion of ApoE ko mice (P<0.05). The present findings demonstrate an important role for UT in the pathogenesis of atherosclerosis. The use of UT receptor antagonists may provide a beneficial tool in the management of this debilitating disease process.