G-Protein-Coupled Receptor 35 Is a Target of the Asthma Drugs Cromolyn Disodium and Nedocromil Sodium

Abstract

We report that the asthma drugs cromolyn disodium and nedocromil sodium are potent G-protein-coupled receptor 35 (GPR35) agonists. We utilized calcium flux and inositol phosphate accumulation assays to examine the pharmacology of these asthma drugs on the human, mouse and rat GPR35. The compounds were more potent on the human GPR35 than on mouse and rat receptors. In contrast, zaprinast, a known GPR35 agonist, was more potent on mouse and rat GPR35 than the human ortholog. We show by quantitative PCR that GPR35 is expressed in human mast cells, human basophils and human eosinophils. We also demonstrate that GPR35 mRNA is upregulated upon challenge with IgE antibodies. We show that, unlike zaprinast, a potent phosphodiesterase 5 (PDE5) inhibitor, cromolyn disodium and nedocromil sodium lack inhibitory activity towards PDE5. These findings suggest that GPR35 may play an important role in mast cell biology and be a potential target for the treatment of asthma.

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

“…Previous studies showed that the antiasthma and antiallergic agents cromolyn disodium (Jenkins et al, 2010;Yang et al, 2010) and nedocromil sodium (Yang et al, 2010) are modestly potent agonists of GPR35. This was confirmed in Mast Cell Stabilizers and GPR35 a PathHunter human GPR35a-b-arrestin-2 interaction and complementation assay (Table 1), with nedocromil sodium (EC 50 5 0.97 6 0.09 mM) being approximately 3-fold more potent than cromolyn disodium (EC 50 5 2.98 6 1.27 mM).…”

“…This was confirmed in Mast Cell Stabilizers and GPR35 a PathHunter human GPR35a-b-arrestin-2 interaction and complementation assay (Table 1), with nedocromil sodium (EC 50 5 0.97 6 0.09 mM) being approximately 3-fold more potent than cromolyn disodium (EC 50 5 2.98 6 1.27 mM). Because GPR35 is expressed by human mast cells and levels are reportedly upregulated by exposure to the allergic stimulus IgE (Yang et al, 2010), we set out to investigate whether other antiallergic ligands and mast cell stabilizers might also act as agonists at GPR35 and, if so, potentially provide a common mode of action. Bufrolin (Fig.…”

“…Glu6.58Arg, Ser7.32Arg pEC antiallergenic drugs cromolyn disodium (Jenkins et al, 2010;Yang et al, 2010) and nedocromil sodium (Yang et al, 2010) have been shown to have agonist activity at GPR35. Although these drugs have modest potency, this encouraged us to explore the possibility that other drugs with similar functional pharmacology might also be GPR35 agonists.…”

“…The antiasthma and antiallergic agents cromolyn disodium (Jenkins et al, 2010;Yang et al, 2010) and nedocromil sodium (Yang et al, 2010) were recently shown to act as moderately potent agonists of GPR35. These ligands are both di-acids with marked mirror image symmetry (Fig.…”

Antagonists of GPR35 Display High Species Ortholog Selectivity and Varying Modes of Action

“…The antiasthma medicine and histamine sensitizer cromolyn disodium ( Fig. 1) (Jenkins et al, 2010;Yang et al, 2010) also acted as an agonist with efficacy equal to that of zaprinast at all three species orthologs. In this case ligand potency was lower, but was relatively similar between the human and rat orthologs with pEC 50 ϭ 4.78 Ϯ 0.10 (mean Ϯ S.E.M.…”