Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity.
Known agonists of the orphan receptor GPR35 are kynurenic acid, zaprinast, 5-nitro-2-(3-phenylproplyamino) benzoic acid, and lysophosphatidic acids. Their relatively low affinities for GPR35 and prominent off-target effects at other pathways, however, diminish their utility for understanding GPR35 signaling and for identifying potential therapeutic uses of GPR35. In a screen of the Prestwick Library of drugs 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 hydroxyzine pamoate (Vistaril) and imipramine pamoate (Tofranil-PM); and the peptide hormones triptorelin pamoate (Trelstar) and octreotide pamoate (OncoLar). We have found that pamoic acid induces a G(i/o)-linked, GPR35-mediated increase in the phosphorylation of extracellular signal-regulated kinase 1/2, recruitment of β-arrestin2 to GPR35, and internalization of GPR35. 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 methyl-5-[(tert-butylcarbamothioylhydrazinylidene)methyl]-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (CID2745687). Pamoic acid and potent antagonists such as 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.
Zhao
Pingwei
P
Department of Anatomy and Cell Biology, Center for Substance Abuse Research, Temple University School of Medicine, 3420 North Broad St, Philadelphia, PA 19140, USA.
Sharir
Haleli
H
Kapur
Ankur
A
Cowan
Alan
A
Geller
Ellen B
EB
Adler
Martin W
MW
Seltzman
Herbert H
HH
Reggio
Patricia H
PH
Heynen-Genel
Susanne
S
Sauer
Michelle
M
Chung
Thomas D Y
TD
Bai
Yushi
Y
Chen
Wei
W
Caron
Marc G
MG
Barak
Larry S
LS
Abood
Mary E
ME
D000700:Analgesics / Q000008:administration & dosage*; D000818:Animals; D019390:Arrestins / Q000819:agonists / Q000378:metabolism*; D002460:Cell Line; D016503:Drug Delivery Systems / Q000379:methods*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D009284:Naphthols / Q000008:administration & dosage*; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D043562:Receptors, G-Protein-Coupled / Q000819:agonists / Q000378:metabolism*; D048790:Renilla; D000071557:beta-Arrestins
D000700:Analgesics; D019390:Arrestins; C111379:GPR35 protein, human; D009284:Naphthols; D043562:Receptors, G-Protein-Coupled; D000071557:beta-Arrestins; C004368:pamoic acid; D048049:Extracellular Signal-Regulated MAP Kinases
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