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

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