The orally administered anti‐allergic agent, sodium nivimedone (BRL 10833); efficacy in bronchial asthma and effects on IgE, complement and eosinophils.

Lumb, Elizabeth; McHardy, G. J. R.; Kay, A. B.

doi:10.1111/j.1365-2125.1979.tb05911.x

Cited by 4 publications

(1 citation statement)

References 12 publications

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“…Bufrolin (Fig. 1), a compound shown originally to be an effective inhibitor of passive cutaneous anaphylaxis in rats, a model of IgE-induced allergy, was a highly potent agonist of human GPR35a (EC 50 5 2.9 6 0.7 nM) ( Table 1), whereas another antiallergic compound effective in the passive cutaneous anaphylaxis model, sodium nivimedone (BRL10833) (Lumb et al, 1979), although substantially less potent (EC 50 5 1.9 6 0.3 mM), also displayed agonism at human GPR35a (Table 1). Interestingly, lodoxamide ( Fig.…”

Section: Resultsmentioning

confidence: 99%

The Antiallergic Mast Cell Stabilizers Lodoxamide and Bufrolin as the First High and Equipotent Agonists of Human and Rat GPR35

Mackenzie¹,

Caltabiano

Kent

et al. 2013

Mol Pharmacol

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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.

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Section: Resultsmentioning

confidence: 99%