GPR35

Ligands

Endogenous ligands

Although GPR35 is still considered an orphan receptor, there have been attempts to deorphanize it by identifying endogenous molecules that can activate the receptor. All of the currently proposed ligands are either unselective towards GPR35, or they lack high potency, a characteristic feature of natural ligands. The following list includes the most prominent examples:

• kynurenic acid
• LPA species
• cyclic guanosine monophosphate
• DHICA
• T3
• reverse T3

Synthetic agonists

Other synthetic agonists of GPR35 include:

• cromoglicic acid
• nedocromil
• pamoic acid
• zaprinast
• lodoxamide
• bufrolin

Zaprinast is currently the gold standard in the biochemical evaluation of novel synthetic GPR35 agonists, because it remains potent in an animal model. Most other known agonists display high selectivity towards the human GPR35 orthologue. This phenomenon is well established for other GPCRs and complicates the development of pharmaceutical drugs.

Antagonists

Antagonists of GPR35 include:

• ML145 (CID-2286812)
• ML144 (CID-1542103)

Both ML145 and ML144 unfurl their antagonistic activity through inverse agonism. They are, however, highly species-selective, and practically inactive at the rodent receptor orthologues.

Clinical significance

Deletion of the GPR35 gene may be responsible for brachydactyly mental retardation syndrome and is mutated in 2q37 monosomy and 2q37 deletion syndrome. In one study GPR35 was recognised as a potential oncogene in stomach cancer.

References

References

1. (January 1998). "Discovery of three novel G-protein-coupled receptor genes". Genomics.
2. (2015-03-10). "G protein-coupled receptor 35: an emerging target in inflammatory and cardiovascular disease". Frontiers Media SA.
3. (October 2010). "Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity". American Society for Pharmacology & Experimental Therapeutics (ASPET).
4. (2009-02-17). "Kynurenic acid as a ligand for orphan G protein-coupled receptor GPR35". The Journal of Biological Chemistry.
5. (June 2013). "Screening β-arrestin recruitment for the identification of natural ligands for orphan G-protein-coupled receptors". SAGE Publications.
6. (2012-04-20). "Multiple tyrosine metabolites are GPR35 agonists". Springer Nature.
7. (2010). "G-protein-coupled receptor 35 is a target of the asthma drugs cromolyn disodium and nedocromil sodium". S. Karger AG.
8. (September 2006). "Zaprinast, a well-known cyclic guanosine monophosphate-specific phosphodiesterase inhibitor, is an agonist for GPR35". FEBS Letters.
9. (January 2014). "The antiallergic mast cell stabilizers lodoxamide and bufrolin as the first high and equipotent agonists of human and rat GPR35". Molecular Pharmacology.
10. (September 2013). "Characterization of new G protein-coupled adenine receptors in mouse and hamster". Springer Nature.
11. (April 2012). "Benzothiazinones: a novel class of adenosine receptor antagonists structurally unrelated to xanthine and adenine derivatives". American Chemical Society (ACS).
12. (2010). "Selective GPR35 Antagonists - Probes 1 & 2". National Center for Biotechnology Information (US).
13. (December 2012). "Antagonists of GPR35 display high species ortholog selectivity and varying modes of action". American Society for Pharmacology & Experimental Therapeutics (ASPET).
14. (December 2004). "Molecular delineation of deletions on 2q37.3 in three cases with an Albright hereditary osteodystrophy-like phenotype". Clinical Genetics.
15. (February 2004). "Cloning of a G-protein-coupled receptor that shows an activity to transform NIH3T3 cells and is expressed in gastric cancer cells". Cancer Science.