The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat gpr35

Mackenzie, A.E. et al. (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), pp. 91-104. (doi:10.1124/mol.113.089482)

Mackenzie, A.E. et al. (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), pp. 91-104. (doi:10.1124/mol.113.089482)

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Publisher's URL: http://dx.doi.org/10.1124/mol.113.089482

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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Milligan, Professor Graeme and Nicklin, Professor Stuart and Caltabiano, Dr Gianluigi and Jenkins, Mrs Laura and Hudson, Dr Brian and Mackenzie, Miss Amanda
Authors: 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., and Milligan, G.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
Journal Name:Molecular Pharmacology
Journal Abbr.:Mol. Pharmacol.
Publisher:American Society for Pharmacology and Experimental Therapeutics
ISSN:0026-895X
ISSN (Online):1521-0111

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