Urotensin-II was originally isolated from the goby urophysis in the 1960s as a vasoactive peptide with a prominent role in cardiovascular homeostasis. The identification of human isoform of urotensin-II and its specific UT receptor by Ames et al. in 1999 led to investigating the putative role of the interaction U-II/UT receptor in multiple pathophysiological effects in humans. Since urotensin-II is widely expressed in several peripheral tissues including cardiovascular system, the design and development of novel urotensin-II analogues can improve knowledge about structure-activity relationships (SAR). In particular, since the modulation of the U-II system offers a great potential for therapeutic strategies related to the treatment of several diseases, like cardiovascular diseases, the research of selective and potent ligands at UT receptor is more fascinating. In this paper, we review the developments of peptide and nonpeptide U-II structures so far developed in order to contribute also to a more rational and detectable design and synthesis of new molecules with high affinity at the UT receptor. 1. Introduction Urotensin-II (U-II) belongs to a series of regulatory neuropeptides first isolated from the urophysis of the teleost fish Gillichthys mirabilis by Karl Lederis and Howard Bern in the 1960s. This cyclic peptide derived from goby fish, H-Ala-Gly-Thr-Ala-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH, was originally characterized on the basis of its interesting smooth muscle contracting and hypertensive effects. It has been long considered that U-II was exclusively produced by the fish urophysis [1]. However, the identification of U-II from the brain of a frog [2, 3] has shown that the cDNA encoding prepro-U-II exists in several species of vertebrates. Moreover, the gene is expressed not only in the caudal portion of the spinal cord but also in brain neurones, from frogs to humans [4]. In fact, urotensin-II isopeptides are present in several species of vertebrates, and although the amino acid sequence in the N-terminus of urotensin-II peptides diverges across species, the cyclic hexapeptide sequence, c[Cys-Phe-Trp-Lys-Tyr-Cys], is conserved in all isoforms (Figure 1, orange residues). Figure 1: A comparison of urotensin-II (U-II) isopeptides sequences isolated from different species of vertebrates. The length of urotensin-II peptides is variable across species and it ranged from 17 amino acid residues in mice to 11 in humans, depending on the proteolytic cleavages that occur in precursors. The N-terminus region of U-II is highly variable among animal species
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