Orthologue selectivity and ligand bias: translating the pharmacology of GPR35

GPR35 is a poorly characterized G protein-coupled receptor (GPCR) that has been suggested as a potential therapeutic target for the treatment of diabetes, hypertension and asthma. Two endogenously produced ligands have been suggested as activators of GPR35, although the relevance of these remains unclear. Recently, a series of surrogate agonist ligands and the first antagonists of GPR35 have been identified. However, marked differences in the potency of agonists at species orthologues of GPR35 have been noted, and this presents substantial challenges in translating the pharmacology at the cloned human receptor to ex vivo and in vivo studies of the physiological function of this receptor in animal models. Currently identified agonists will probably not display high selectivity for GPR35. By contrast, comparisons of the potency of ligands at species orthologues of GPR35 have provided insight into the nature of the ligand binding pocket and could result in the identification of more potent and selective ligands.