Identification of cysteinyl-leukotriene-receptor 1 antagonists as ligands for the bile acid receptor GPBAR1.

Abstract

The cysteinyl leukotrienes (CysLTs), i.e. LTC4, LTD4 and LTE4, are a family of proinflammatory agents synthesized from the arachidonic acid. In target cells, these lipid mediators bind to the cysteinyl leukotriene receptors (CysLTR), a family of seven transmembrane G-protein coupled receptors. The CysLT1R is a validated target for treatment of pulmonary diseases and several selective antagonists for this receptor, including montelukast, zafirlukast and pranlukast, have shown effective in the management of asthma. Nevertheless, others CysLT1R antagonists, such as the alpha-pentyl-3-[2-quinolinylmethoxy] benzyl alcohol (REV5901), have been extensively characterized without reaching sufficient priority for clinical development. Since drug reposition is an efficient approach for maximizing investment in drug discovery, we have investigated whether CysLT1R antagonists might exert off-target effects. In the report we demonstrate that REV5901 interacts with GPBAR1, a well characterized cell membrane receptor for secondary bile acids. REV5901 transactivates GPBAR1 in GPBAR1-transfected cells with an EC50 of 2.5 µM and accommodates the GPBAR1 binding site as shown by in silico analysis. Exposure of macrophages to REV5901 abrogates the inflammatory response elicited by bacterial endotoxin in a GPBAR1-dependent manner. In vivo, in contrast to montelukast, REV5901 attenuates inflammation and immune dysfunction in rodent models of colitis. The beneficial effects exerted by REV5901 in these models were abrogated by GPBAR1 gene ablation, confirming that REV5901, a shelved CysLT1R antagonist, is a GPBAR1 ligand. These data ground the basis for the development of novel hybrid ligands designed for simultaneous modulation of CysTL1R and GPBAR1.

• Authors: Michele Biagioli, Adriana Carino, Silvia Marchianò, Rosalinda Roselli, Cristina Di Giorgio, Martina Bordoni, Chiara Fiorucci, Valentina Sepe, Paolo Conflitti, Vittorio Limongelli, Eleonora Distrutti, Monia Baldoni, Angela Zampella, Stefano Fiorucci
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 177 Pg. 113987 (07 2020) ISSN: 1873-2968 [Electronic] England
• PMID: 32330496 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• 6-ethyl-24-norcholane-3,7,23-triol-23 sulfate
• Acetates
• Anti-Inflammatory Agents, Non-Steroidal
• Bile Acids and Salts
• Cyclopropanes
• GPBAR1 protein, human
• Leukotriene Antagonists
• Quinolines
• Receptors, G-Protein-Coupled
• Receptors, Leukotriene
• Recombinant Fusion Proteins
• Sulfides
• alpha-pentyl-3-(2-quinolinylmethoxy)benzenemethanol
• Leukotriene C4
• Leukotriene D4
• Leukotriene E4
• Luciferases
• leukotriene D4 receptor
• montelukast

Topics

• Acetates (pharmacology)
• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Bile Acids and Salts (pharmacology)
• Colitis (drug therapy, genetics, metabolism, pathology)
• Cyclopropanes
• Disease Models, Animal
• Gene Expression
• Genes, Reporter
• HEK293 Cells
• Hep G2 Cells
• Humans
• Leukotriene Antagonists (pharmacology)
• Leukotriene C4 (metabolism)
• Leukotriene D4 (metabolism)
• Leukotriene E4 (metabolism)
• Luciferases (genetics, metabolism)
• Mice
• Mice, Knockout
• Molecular Docking Simulation
• Quinolines (pharmacology)
• RAW 264.7 Cells
• Receptors, G-Protein-Coupled (antagonists & inhibitors, chemistry, genetics, metabolism)
• Receptors, Leukotriene (chemistry, genetics, metabolism)
• Recombinant Fusion Proteins (genetics, metabolism)
• Sulfides