The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35

Amanda E. MacKenzie, Gianluigi Caltabiano, Toby C. Kent, Laura Jenkins, Jennifer E. McCallum, Brian D. Hudson, Stuart A. Nicklin, Lindsay Fawcett, Rachel Markwick, Steven J. Charlton, Graeme Milligan

Research output: Contribution to journalArticleResearchpeer-review

28 Citations (Scopus)

Abstract

Lack of high potency agonists has restricted analysis of the G protein-coupled receptor GPR35. Moreover, marked variation in potency and/or affinity of current ligands between human and rodent orthologs of GPR35 has limited their productive use in rodent models of physiology. Based on the reported modest potency of the antiasthma and antiallergic ligands cromolyn disodium and nedocromil sodium, we identified the related compounds lodoxamide and bufrolin as high potency agonists of human GPR35. Unlike previously identified high potency agonists that are highly selective for human GPR35, both lodoxamide and bufrolin displayed equivalent potency at rat GPR35. Further synthetic antiallergic ligands, either sharing features of the standard surrogate agonist zaprinast, or with lodoxamide and bufrolin, were also shown to display agonism at either human or rat GPR35. Because both lodoxamide and bufrolin are symmetric di-acids, their potential mode of binding was explored via mutagenesis based on swapping between the rat and human ortholog nonconserved arginine residues within proximity of a key conserved arginine at position 3.36. Computational modeling and ligand docking predicted the contributions of different arginine residues, other than at 3.36, in human GPR35 for these two ligands and were consistent with selective loss of potency of either bufrolin or lodoxamide at distinct arginine mutants. The computational models also suggested that bufrolin and lodoxamide would display reduced potency at a low-frequency human GPR35 single nucleotide polymorphism. This prediction was confirmed experimentally. Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics.
Original languageEnglish
Pages (from-to)91-104
JournalMolecular Pharmacology
Volume85
Issue number1
DOIs
Publication statusPublished - 1 Jan 2014

Fingerprint Dive into the research topics of 'The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35'. Together they form a unique fingerprint.

  • Cite this

    MacKenzie, A. E., Caltabiano, G., Kent, T. C., Jenkins, L., McCallum, J. E., Hudson, B. D., Nicklin, S. A., Fawcett, L., Markwick, R., Charlton, S. J., & Milligan, G. (2014). The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35. Molecular Pharmacology, 85(1), 91-104. https://doi.org/10.1124/mol.113.089482