+ Site Statistics
References:
54,258,434
Abstracts:
29,560,870
PMIDs:
28,072,757
+ Search Articles
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ PDF Full Text
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Translate
+ Recently Requested

Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II



Identification of nonpeptidic urotensin II receptor antagonists by virtual screening based on a pharmacophore model derived from structure-activity relationships and nuclear magnetic resonance studies on urotensin II



Journal of Medicinal Chemistry 45(9): 1799-1805, April 25



The vasoactive cyclic 11-amino acid peptide urotensin II (U-II) has recently been discovered as the endogenous ligand of the orphan G-protein-coupled receptor GPR14. As U-II might be involved in the regulation of cardiovascular homeostasis and pathology, a nonpeptidic GPR14/U-II antagonist is of considerable basic and therapeutic interest. We have performed structure-activity relationship studies on U-II by investigating 25 peptide analogues to mobilize intracellular calcium in GPR14-transfected CHO cells, demonstrating that only the side chains of the residues Trp-7, Lys-8, and Tyr-9 are required for receptor recognition and activation. The solution structure of U-II derived by nuclear magnetic resonance has served as a structural template for a three-dimensional three point pharmacophore query for the virtual screening of the Aventis compound repository for nonpeptidic U-II receptor antagonists. Highly active lead compounds of six different scaffold classes could be identified, antagonizing the biological activity of U-II in vitro. The most potent compound identified by the virtual screening approach, 1-(3-carbamimidoyl-benzyl)-4-methyl-1H-indole-2-carboxylic acid (naphthalen-1-ylmethyl)amide, reveals an IC(50) of 400 nM in a functional fluorometric imaging plate reader assay and constitutes a promising lead.

(PDF emailed within 0-6 h: $19.90)

Accession: 010787103

Download citation: RISBibTeXText

PMID: 11960491

DOI: 10.1021/jm0111043


Related references

Three-dimensional model of the human urotensin-II receptor: docking of human urotensin-II and nonpeptide antagonists in the binding site and comparison with an antagonist pharmacophore model. Proteins 73(1): 173-184, 2008

Structure-activity relationships of a novel series of urotensin II analogues: identification of a urotensin II antagonist. Journal of Medicinal Chemistry 49(24): 7234-7238, 2006

Characterization of urotensin II, distribution of urotensin II, urotensin II-related peptide and UT receptor mRNAs in mouse: evidence of urotensin II at the neuromuscular junction. Journal of Neurochemistry 107(2): 361-374, 2008

Nonpeptide Urotensin-II receptor agonists and antagonists: review and structure-activity relationships. Peptides 29(5): 680-690, 2007

Nonpeptidic urotensin-II receptor antagonists I: in vitro pharmacological characterization of SB-706375. British Journal of Pharmacology 145(5): 620-635, 2005

Identification of novel cannabinoid CB1 receptor antagonists by using virtual screening with a pharmacophore model. Journal of Medicinal Chemistry 51(8): 2439-2446, 2008

Expression of urotensin II and urotensin II receptor mRNAs in various human tumor cell lines and secretion of urotensin II-like immunoreactivity by SW-13 adrenocortical carcinoma cells. Peptides (New York) 22(7): 1175-1179, 2001

Increased expression of urotensin II, urotensin II-related peptide and urotensin II receptor mRNAs in the cardiovascular organs of hypertensive rats: comparison with endothelin-1. Peptides 30(6): 1124-1129, 2009

Inhibitory effects of putative peptidic urotensin-II receptor antagonists on urotensin-II-induced contraction of cat isolated respiratory smooth muscle. European Journal of Pharmacology 516(3): 276-281, 2005

Urotensin core mimics that modulate the biological activity of urotensin-II related peptide but not urotensin-II. Bioorganic and Medicinal Chemistry Letters 27(15): 3412-3416, 2017

Solution structure of urotensin-II receptor extracellular loop III and characterization of its interaction with urotensin-II. Peptides 29(5): 700-710, 2008

International Union of Basic and Clinical Pharmacology. XCII. Urotensin II, urotensin II-related peptide, and their receptor: from structure to function. Pharmacological Reviews 67(1): 214-258, 2015

Definition of new pharmacophores for nonpeptide antagonists of human urotensin-II. Comparison with the 3D-structure of human urotensin-II and URP. Journal of Chemical Information and Modeling 47(2): 602-612, 2007

Identification of potential Gly/NMDA receptor antagonists by cheminformatics approach: a combination of pharmacophore modelling, virtual screening and molecular docking studies. Sar and Qsar in Environmental Research 27(2): 125-145, 2016

Identification of Novel Protein Kinase Receptor Type 2 Inhibitors Using Pharmacophore and Structure-Based Virtual Screening. Molecules 23(2), 2018