Selective GPR35 Antagonists - Probes 1 & 2

Excerpt

Although many known receptors that regulate addiction have been pharmacologically and biochemically well characterized, some orphan receptors with homology to known receptors of abuse (i.e. GPR35) remain uncharacterized. GPR35 is a G-protein coupled receptor, first identified in 1998 after a screen of a human genomic library. More recent RT-PCR studies have now confirmed the presence of GPR35 in dorsal root ganglion, the cerebellum and brain, as well as GPR35b, which was cloned from a human whole brain cDNA library. Thus, GPR35 regulation appears to have profound physiological and pathophysiological implications. In line with the specific aim of this project, the identified probes ML145 (CID-2286812) and ML144 (CID-1542103) represent selective antagonists for GPR35, but not for the related GPR55 orphan receptor, supporting the hypothesis that they do not produce non-specific interference with signaling directly at or downstream of the β-arrestin signaling pathway. These probes will serve as novel tools to delineate the biochemistry of GPR35 as potential therapeutics to selectively target pathways underlying pain and to enhance our understanding of the molecular basis of addiction.