Urotensin II^(4–11) Azasulfuryl Peptides: Synthesis and Biological Activity

Abstract

Cyclic azasulfuryl (As) peptide analogs of the urotensin II (UII, 1, H-Glu-Thr-Pro-Asp-c[Cys-Phe-Trp-Lys-Tyr-Cys]-Val-OH) fragment 4-11 were synthesized to explore the influences of backbone structure on biological activity. N-Aminosulfamides were inserted as surrogates of the Trp(7) and Lys(8) residues in the biologically relevant Trp-Lys-Tyr triad. A combination of solution- and solid-phase methods were used to prepare novel UII((4-11)) analogs 6-11 by routes featuring alkylation of azasulfuryl-glycine tripeptide precursors to install various side chains. The pharmacological profiles of derivatives 6-11 were tested in vitro using a competitive binding assay and ex vivo using a rat aortic ring bioassay. Although the analogs exhibited weak affinity for the urotensin II receptor (UT) without agonistic activity, azasulfuryl-UII((4-11)) derivatives 7-9 reduced up to 50% of the effects of UII and urotensin II-related peptide (URP) without affecting their potency.

Development of Macrocyclic Peptidomimetics Containing Constrained α,α-Dialkylated Amino Acids with Potent and Selective Activity at Human Melanocortin Receptors

“…20,21 In particular, the resins were washed with DCM (2 mL × 3), suspended in a solution of Pd(PPh 3 ) 4 (0.15 equiv) and N , N ′-dimethylbarbituric acid (NDMBA) (7 equiv) in 3:2 dry DCM/DMF (v/v), and placed in a 20 mL μ W reaction vessel. The vessel was sealed and heated to 40 °C using μ W irradiation for 5 min.…”

New directions for urotensin II receptor ligands

“…Over the past few years, our search for new modulators led to the discovery of an azasulfuryl urotensin II derivative, i.e. [AsNal(2') 7 ]UII (4–11) (Figure ), that can exert a probe‐dependent action on UII and URP biological activity . Altogether, modification/substitution of the Trp residue in UII and URP represent a new avenue toward the conception of UT ligands with unique pharmacological profile.…”

“…So far, none of the UT antagonists has been investigated for their ability to also block URP‐mediated function. However, recently developed peptidic and non‐peptidic UT antagonists have demonstrated a wide range of activity against UII‐ and URP‐mediated function . For instance, R‐4a (Figure ) inhibited completely hUII‐induced contractions but increased tremendously URP‐associated vasoconstriction .…”

Total flavones of Rhododendron simsii Planch flower protect isolated rat heart from ischaemia-reperfusion injury and its mechanism of UTR-RhoA-ROCK pathway inhibition

“…Urotensin‐II (U‐II) is a kind of growth hormone‐like neuropeptide, which is ubiquitous in many tissues and organs of mammals, including humans . A large number of studies have shown that the combination of human U‐II (hUII) and its receptor (urotensin receptor, UTR) can produce various biological effects and play an important role in the occurrence and the development of various cardiovascular diseases . RhoA is one of the effectors of the small GTP‐binding protein.…”

“…[5] A large number of studies have shown that the combination of human U-II (hUII) and its receptor (urotensin receptor, UTR) can produce various biological effects and play an important role in the occurrence and the development of various cardiovascular diseases. [6,7] RhoA is one of the effectors of the small GTP-binding protein. RhoA and its downstream target molecules Rho-related coiled-coil-forming protein kinase (ROCK) participate in the regulation of a variety of physiological functions and various pathological processes.…”