Grant: Operating Grant

The urotensin II receptor (UT) plays important roles in the heart, kidneys, pancreas, adrenal gland, and central nervous system. The receptor is known to bind to two endogenous cyclic peptide ligands: urotensin II (UII) and urotensin II-related peptide (URP). These ligands and the parent receptor have been implicated in heart disease, metabolic syndrome, and kidney failure. For example, in the cardiovascular system, UII acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator; however, in disease states, this constriction-dilation equilibrium is disrupted. Their specific influences on UT have been difficult to decipher due to a dearth in molecules that can selectively block the activity of UII and URP; however, it is suspected that their functional selectivity leads to differential participation in specific cardiovascular disease pathology. Our collaborative research has recently identified a novel class of receptor modulators that can differentiate the effects of UII and URP. Pyrrolodiazepin-2-one small molecules have been conceived in our laboratory which mimic the side chain orientations and backbone conformation of a biologically relevant tripeptide motif common to both endogenous urotensin receptor (UT) ligands. In preliminary research, we have found that our pyrrolodiazepin-2-ones can modulate selectively and differentially the contractile effects of UII and URP ex vivo. Considering the importance of UT and its ligands in cardiovascular diseases, these modulators offer unique potential for dissecting the different biological pathways mediated by UII and URP in normal physiology and during disease pathology. A plan is proposed for improving ligand potency to develop probes and ideally therapeutics to treat cardiovascular diseases by an interdisciplinary approach featuring organic synthesis, in vitro and ex vivo screening, and animal models of atherosclerosis.