Discovery of the First Nonpeptide Agonist of the GPR14/Urotensin-II Receptor:  3-(4-Chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954)

Croston, Glenn; Olsson, Roger; Currier, Erika A.; Burstein, Ethan S.; Weiner, David M.; Nash, Norman R.; Severance, Daniel L.; Allenmark, Stig; Thunberg, Linda; Nong, Jian; Mohell, Nina; O’Dowd, Brian F.; Brann, Mark R.; Hacksell, Uli

doi:10.1021/jm025551+

Cited by 60 publications

(36 citation statements)

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“…Nevertheless, the 3D information might be very useful for understanding the binding process of existing leads, as shown by docking studies performed with the nonpeptidic UII agonist AC-7954 (Lavecchia et al, 2005) (Fig. 11, compound 17; Acadia Pharmaceuticals, San Diego, CA; EC 50 : 316 nM for the racemic mixture) (Croston et al, 2002). Noteworthy, AC-7954 is the precursor of the potent UT agonists (+)-FL68 (EC 50 : 50 nM), a 6,7-dimethylated derivative of the lead compound (Lehmann et al, 2005), as well as (+)-FL104 (Fig.…”

Section: Design Of Nonpeptidic Urotensin II Receptor Agonists and mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

et al. 2014

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Section: Design Of Nonpeptidic Urotensin II Receptor Agonists and mentioning

confidence: 99%

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

et al. 2014

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“…Palosuran has been identifi ed as a potent nonpeptide, orally active antagonist of the human UT receptor, binding studies showed the ligand to have 100-fold greater affi nity for human UT receptor over rat UT receptor [29]. Other synthetic ligands, e.g., agonists: AC-7954,1 [30] and antagonists: SB-706375 [31] have been identifi ed. For a review of UT receptor antagonists the reader is directed to [32].…”

Section: Introductionmentioning

confidence: 99%

Role of urotensin II and its receptor in health and disease

2007

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Urotensin II (U-II) is currently the most potent vasoconstrictor identified. This action is brought about via activation of a G(q/11)-protein coupled receptor (UT receptor). U-II activation of the UT receptor increases inositol phosphate turnover and intracellular Ca(2+). In addition to producing vasoconstriction, dilation and ionotropic effects have also been described. There is considerable variation in the responsiveness of particular vascular beds from the same and different species, including humans. Receptors for U-II are located peripherally on vascular smooth muscle (contractile responses) and endothelial cells (dilatory responses via nitric oxide). In humans, plasma U-II is elevated in heart failure, renal failure, liver disease, and diabetes. Iontophoresis of U-II in healthy volunteers produces vasodilation (of the forearm) while in patients with heart failure or hypertension a constriction is observed. To date there is only one clinical study using a UT receptor antagonist (palosuran) in diabetic patients with macroalbuminuria. This antagonist reduced albumin excretion, probably by increasing renal blood flow. Studies in other disease conditions are eagerly awaited. In summary, the U-II / UT receptor system has clinical potential, and for the anesthesiologist, this novel peptide-receptor system may be of use in the intensive care unit.

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“…Urotensin II has recently been shown to be upregulated in infarcted rat heart (28) and in congestive heart failure in humans (11), suggesting a possible role of urotensin II in cardiac remodeling. Agonists (8,17) and antagonists (2,12,24) for GPR14 have been assumed as tools for pharmacological research and potential drug leads for the treatment of cardiovascular diseases. These reports give rise to the hypothesis that rat myocardium contains GPR14 receptor, which may be responsible for the biological effects of urotensin II in this tissue.…”

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Cellular distribution of GPR14 and the positive inotropic role of urotensin II in the myocardium in adult rat

Gong

Wang²,

Zhu³

et al. 2004

Journal of Applied Physiology

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. Cellular distribution of GPR14 and the positive inotropic role of urotensin II in the myocardium in adult rat. J Appl Physiol 97: 2228 -2235 doi:10.1152/japplphysiol.00540.2004.-Urotensin II is a cyclic neuropeptide recently shown to play a role via its receptor GPR14 in regulating vascular tone in the mammalian cardiovascular system. The existence of GPR14 in rat heart has been validated by ligand binding assay and RT-PCR. In the present study, we investigated the cellular distribution of GPR14 protein in rat heart by using immunohistochemistry and confocal microscopic immunofluorescence double staining with antipeptide polyclonal antibodies against GPR14 and cell type markers for myocytes and endothelial cells. The direct effect of urotensin II on left ventricular contractility was further evaluated in isolated left ventricular papillary muscles of the rat. In paraffin-embedded heart sections, positive immunohistochemical staining was observed in the left ventricle but not in the right ventricle and atria. Immunofluorescence double staining revealed the cardiac myocyte as the only cell type expressing GPR14 protein in frozen heart sections as well as in isolated cardiac myocytes. There was no visible signal for GPR14 in intramyocardial coronary arteries and capillaries. The existence of GPR14 protein in rat heart was further validated by immunoprecipitation and Western blot analysis. In isolated rat left ventricular papillary muscle preparations, urotensin II induced an increase in active contractile force. GPR14 mRNA was also detected in rat heart by RT-PCR. These data provide the first direct evidence for the cellular localization of GPR14 receptor protein and a positive inotropic effect of urotensin II in normal rat heart. urotensin II; GPR14; cardiac myocyte; double staining; inotropic effect UROTENSIN II, A CYCLIC NEUROPEPTIDE initially isolated from the urophysis of teleost fish (3), has recently been cloned in several mammalian species including human. Gibson et al. (15) first reported a role of urotensin II in regulating cardiovascular function in the rat. More recently, urotensin II was identified in both the vascular and cardiac tissues and shown to effectively constrict the isolated arteries from rats (14), rabbits (10), dogs (10), pigs (10), nonhuman primates (1), and humans (20). In several recent reports, urotensin II has been recognized as the most potent vasoconstrictor with 8-to 110-fold potent than endothelin 1 (9). On the other hand, however, the reported depressor and regionally selective vasodilator effects (4, 13, 27) of urotensin II endow its vasoactive effects with complexity. Systemic administration of human urotensin II to anesthetized monkeys resulted in a complex dose-dependent hemodynamic response including a decrease in cardiac contractility and stroke volume with a concomitant increase in total peripheral resistance, leading eventually to fatal cardiovascular collapse (1). Intravenous bolus injection of human urotensin II into the rat produced a dose-dependent decrease in mean ...

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Discovery of the First Nonpeptide Agonist of the GPR14/Urotensin-II Receptor: 3-(4-Chlorophenyl)-3-(2- (dimethylamino)ethyl)isochroman-1-one (AC-7954)

Cited by 60 publications

References 20 publications

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, Urotensin II–Related Peptide, and Their Receptor: From Structure to Function

Role of urotensin II and its receptor in health and disease

Cellular distribution of GPR14 and the positive inotropic role of urotensin II in the myocardium in adult rat

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