GPR35 is a poorly characterized member of the rhodopsin-like class A subfamily of G protein-coupled receptors (GPCRs), which has attracted attention as a possible therapeutic target in conditions ranging from diabetes and cardiovascular disease to inflammation and pain. Substantial selectivity in potency of a number of GPR35 agonists has previously been demonstrated between human and rat orthologs of this G protein coupled receptor hindering its understanding. A further limitation in efforts to understand the function of GPR35 is that until recently, no antagonists had been described. This study investigated whether the difference in potency across species was also observed with the GPR35 antagonists methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID-2745687) and 2-hydroxy-4-[4-(5Z)-5-[(E)-2-methyl-3-phenylprop-2-enylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]butanoylamino)benzoic acid (ML-145). Both CID-2745687 and ML-145 competitively inhibited effects of two agonists, cromolyn disodium and zaprinast, at human GPR35. By contrast, neither ML-145 nor CID-2745687 was able to effectively antagonize effects of either zaprinast or cromolyn disodium in either rodent ortholog of GPR35. These results demonstrate that marked species selectivity of ligands at GPR35 is not restricted to agonists and that considerable care is required to select appropriate ligands to explore the function of GPR35 in nonhuman cells and tissue.
See article at J Pharmacol Exp Ther 2012, 343:683–695.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics