Urotensin-II Receptor Antagonists

Abstract

Urotensin-II (U-II) is a "somatostatin-like" cyclic neuropeptide which was originally isolated from goby fish urophysis, and subsequently identified in other species, including man. The interest in human U-II (hU-II) has grown enormously in the last few years, following the identification of a specific human receptor (formerly identified as the GPR14/SENR orphan receptor), now referred to as UT receptor. The U-II/UT system seems to play an important role in cardiovascular functions. hU-II vasoconstrictive potency is reported to be an order of magnitude greater than that of endothelin-1 (ET-1), which would make it the most potent mammalian vasoconstrictor identified to date. hU-II also exerts potent inotropic effects in the human heart in vitro. On the basis of its spectrum of activities, hU-II has been suggested to modulate cardiovascular homeostasis and possibly to be involved in certain cardiovascular pathologies. Central nervous effects of U-II have also been described, in particular, intracerebroventricular administration promotes anxiogenic-like behaviors in rodents. Furthermore, UT receptor overexpression has been observed in some tumor cell lines. Therefore, specific and selective UT receptor antagonists provide useful tools for investigating the (patho)physiological role(s) of the U-II/UT receptor system. In this review we aim to provide an overview of the research in the area of UT receptor antagonists as well as the progress in understanding the role of the U-II/UT system in human (patho)physiology.

Predicted Ligands for the Human Urotensin‐II G Protein‐Coupled Receptor with Some Experimental Validation

“…Alanine scans of the native undecapeptide revealed that the W 7 K 8 Y 9 triad is required for receptor recognition and activation 4. Correlating this pharmacophore study, all reported compounds of hUT 2 R antagonists contain a basic amino group and at least two aromatic moieties 5. The recently described P5U superagonist, with higher affinity than U‐II at hUT 2 R as well as higher activity in the rat thoracic aorta assay, where a cysteine residue in position 5 is replaced by penicillamine (β,β‐dimethylcystein), adopts a well‐defined type II′ beta‐hairpin structure as determined by nuclear magnetic resonance (NMR) studies 2.…”

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

“…Structure-activity relationship studies (Flohr et al, 2002;Kinney et al, 2002;Brkovic et al, 2003;Labarrère et al, 2003;Chatenet et al, 2004;Guerrini et al, 2005;Leprince et al, 2008;Merlino et al, 2013) led to the discovery of peptide-derived analogs acting as potent agonists or antagonists (Behm et al, 2002;Grieco et al, 2002a;Herold et al, 2003;Patacchini et al, 2003;Carotenuto et al, 2004b;Grieco et al, 2005;Carotenuto et al, 2006;Chatenet et al, 2012Chatenet et al, , 2013a. However, those molecules are usually not considered as the best drug candidates, because their pharmacodynamic and pharmacokinetic properties (bioavailability, metabolic stability, biodistribution) are not optimal.…”

Role of urotensin II and its receptor in health and disease

“…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]. See also Table 1.…”