BACKGROUND AND PURPOSE Recently identified antagonists of the urotensin–II (U‐II) receptor (UT) are of limited utility for investigating the (patho)physiological role of U‐II due to poor potency and limited selectivity and/or intrinsic activity.EXPERIMENTAL APPROACH The pharmacological properties of two novel UT antagonists, GSK1440115 and GSK1562590, were compared using multiple bioassays.KEY RESULTS GSK1440115 (pKi= 7.34–8.64 across species) and GSK1562590 (pKi= 9.14–9.66 across species) are high affinity ligands of mammalian recombinant (mouse, rat, cat, monkey, human) and native (SJRH30 cells) UT. Both compounds exhibited >100‐fold selectivity for UT versus 87 distinct mammalian GPCR, enzyme, ion channel and neurotransmitter uptake targets. GSK1440115 showed competitive antagonism at UT in arteries from all species tested (pA2= 5.59–7.71). In contrast, GSK1562590 was an insurmountable UT antagonist in rat, cat and hUT transgenic mouse arteries (pKb= 8.93–10.12 across species), but a competitive antagonist in monkey arteries (pKb= 8.87–8.93). Likewise, GSK1562590 inhibited the hU‐II‐induced systemic pressor response in anaesthetized cats at a dose 10‐fold lower than that of GSK1440115. The antagonistic effects of GSK1440115, but not GSK1562590, could be reversed by washout in rat isolated aorta. In ex vivo studies, GSK1562590 inhibited hU‐II‐induced contraction of rat aorta for at least 24 h following dosing. Dissociation of GSK1562590 binding was considerably slower at rat than monkey UT.CONCLUSIONS AND IMPLICATIONS Whereas both GSK1440115 and GSK1562590 represent high‐affinity/selective UT antagonists suitable for assessing the (patho)physiological role of U‐II, only GSK1562590 exhibited sustained UT residence time and improved preclinical efficacy in vivo.
