RT Journal Article
SR Electronic
T1 Targeting of the Orphan Receptor GPR35 by Pamoic Acid: a Potent Activator of ERK and β-arrestin2, with Antinociceptive Activity
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.110.066746
DO 10.1124/mol.110.066746
A1 Pingwei Zhao
A1 Haleli Sharir
A1 Ankur Kapur
A1 Alan Cowan
A1 Ellen B Geller
A1 Martin W Adler
A1 Herbert H Seltzman
A1 Patricia H. Reggio
A1 Susanne Heynen-Genel
A1 Michelle Sauer
A1 Thomas D.Y. Chung
A1 Yushi Bai
A1 Wei Chen
A1 Marc G. Caron
A1 Larry S. Barak
A1 Mary E. Abood
YR 2010
UL http://molpharm.aspetjournals.org/content/early/2010/07/22/mol.110.066746.abstract
AB The orphan receptor GPR35 has known agonists, kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproproplyamino) benzoic acid (NPPB), and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off target effects at other pathways, however, diminish their utility for understanding GPR35 signalling and for identifying potential therapeutic uses of GPR35. In a screen of the Prestwick Library of drug and drug-like compounds, we have found that pamoic acid is a potent GPR35 agonist. Pamoic acid is considered by the Food and Drug Administration as an inactive compound that enables long-acting formulations of numerous drugs, such as the antihelminthics, oxantel pamoate and pyrantel pamoate; the psychoactive compounds Vistaril (hydroxyzine pamoate) and Tofranil-PM (imipramine pamoate), and the peptide hormones Trelstar (triptorelin pamoate) and OncoLar (octreotide pamoate). We have found that pamoic acid induces a Gi/o-linked, GPR35-mediated increase in the phosphorylation of ERK1/2, β-arrestin2 recruitment to GPR35, and GPR35 internalization. In mice it attenuates visceral pain perception indicating an antinociceptive effect possibly through GPR35 receptors. We have also identified in collaboration with the Sanford-Burnham Institute Molecular Libraries Probe Production Center new classes of GPR35 antagonist compounds, including the nanomolar potency antagonist CID2745687. Pamoic acid and potent antagonists like CID2745687 present novel opportunities for expanding the chemical space of GPR35, elucidating GPR35 pharmacology, and stimulating GPR35 associated drug development. Our results indicate that the unexpected biological functions of pamoic acid may yield potential new uses for a common drug constituent.