Aminomethylpiperazines as selective urotensin antagonists

Hilfiker, Mark A.; Zhang, Dao Hua; Dowdell, Sarah E.; Goodman, Krista B.; McAtee, John J.; Dodson, Jason W.; Viet, Andrew Q.; Wang, Gren Z.; Sehon, Clark A.; Behm, David J.; Wu, Zining; Carballo, Luz H.; Douglas, Stephen A.; Neeb, Michael J.

doi:10.1016/j.bmcl.2008.07.067

Cited by 13 publications

(3 citation statements)

References 42 publications

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“…Aminomethylpiperazines derivatives were also drawn out from the structure belonging to κ -opioid receptor agonists [74]. In accordance with this study, optimization of the piperazine moiety provided high affinity urotensin-II receptor antagonists (more than 100-fold selectivity over the κ -opioid receptor) and, among this series, specific compounds inhibited urotensin-induced vasoconstriction in isolated rat aortic ring.…”

Section: Nonpeptide Ligandsmentioning

confidence: 82%

Urotensin-II Ligands: An Overview from Peptide to Nonpeptide Structures

Merlino

Maro

Yousif

et al. 2013

Journal of Amino Acids

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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.

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Section: Nonpeptide Ligandsmentioning

confidence: 82%

Urotensin-II Ligands: An Overview from Peptide to Nonpeptide Structures

Merlino

Maro

Yousif

et al. 2013

Journal of Amino Acids

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“…Furthermore, Lys 8 had been described as a critical residue for U-II activity . Replacement of the U-II disulfide bridge with lactam bridges of different lengths showed that the biological activity of U-II is dependent upon the size of the cyclic structure. , In addition, a considerable number of peptide or small molecule agonistic analogues and of U-II antagonists has been described. ,,− However, a full systematic SAR of U-II using the other 19 natural amino acids at each position of the peptide has not been published to date.…”

Section: Introductionmentioning

confidence: 99%

Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist

et al. 2016

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This study investigated the role of individual U-II amino acid positions and side chain characteristics important for U-IIR activation. A complete permutation library of 209 U-II variants was studied in an activity screen that contained single substitution variants of each position with one of the other 19 proteinogenic amino acids. Receptor activation was measured using a cell-based high-throughput fluorescence calcium mobilization assay. We generated the first complete U-II substitution map for U-II receptor activation, resulting in a detailed view into the structural features required for receptor activation, accompanied by complementary information from receptor modeling and ligand docking studies. On the basis of the systematic SAR study of U-II, we created 33 further short and linear U-II variants from eight to three amino acids in length, including d- and other non-natural amino acids. We identified the first high-potency linear U-II analogues. Urolinin, a linear U-II agonist (nWWK-Tyr(3-NO)-Abu), shows low nanomolar potency as well as improved metabolic stability.

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“…Similarly, piperazine is also a biodynamic heterosystem, and continues to be a target of interest due to its presence in a number of natural and synthetic drugs. Piperazine derivatives have also been reported to exhibit a wide range of biological activities (Li et al, 2008;Hilfiker et al, 2008;Jazayeri et al, 2009;Cunico et al, 2008;Masson et al, 2008;Minarini et al, 2008;Swarup and Rangappa, 2009;Berger et al, 2008;Drizin et al, 2008;Tagat et al, 2001Tagat et al, , 2004Shami et al, 2006;Folkes et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and antimicrobial activity of morpholinyl/piperazinylbenzothiazines

2011

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Structurally diverse morpholinyl/piperazinylbenzothiazines have been synthesized in quantitative yields by the reaction of substituted 1,4-benzothiazines with morpholine/N-(2-hydroxyethyl)piperazine. 1,4-Benzothiazines were prepared by the reaction of substituted 2-aminobenzenethiols with b-ketoesters. The structures of the synthesized compounds were confirmed by their analytical and spectroscopic data. The synthesized compounds were evaluated for their antimicrobial activity against bacterial species; E. coli and Bacillus cereus. Some of the synthesized compounds have shown significant activity against microorganisms.

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Aminomethylpiperazines as selective urotensin antagonists

Cited by 13 publications

References 42 publications

Urotensin-II Ligands: An Overview from Peptide to Nonpeptide Structures

Urotensin-II Ligands: An Overview from Peptide to Nonpeptide Structures

Urolinin: The First Linear Peptidic Urotensin-II Receptor Agonist

Synthesis and antimicrobial activity of morpholinyl/piperazinylbenzothiazines

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