title: Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and β-arrestin2 with antinociceptive activity.
abstract: 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.
authors.affiliation: Department of Anatomy and Cell Biology, Center for Substance Abuse Research, Temple University School of Medicine, 3420 North Broad St, Philadelphia, PA 19140, USA.
authors.forename: Pingwei
authors.initials: P
authors.lastname: Zhao
authors.forename: Haleli
authors.initials: H
authors.lastname: Sharir
authors.forename: Ankur
authors.initials: A
authors.lastname: Kapur
authors.forename: Alan
authors.initials: A
authors.lastname: Cowan
authors.forename: Ellen B
authors.initials: EB
authors.lastname: Geller
authors.forename: Martin W
authors.initials: MW
authors.lastname: Adler
authors.forename: Herbert H
authors.initials: HH
authors.lastname: Seltzman
authors.forename: Patricia H
authors.initials: PH
authors.lastname: Reggio
authors.forename: Susanne
authors.initials: S
authors.lastname: Heynen-Genel
authors.forename: Michelle
authors.initials: M
authors.lastname: Sauer
authors.forename: Thomas D Y
authors.initials: TD
authors.lastname: Chung
authors.forename: Yushi
authors.initials: Y
authors.lastname: Bai
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
authors.forename: Larry S
authors.initials: LS
authors.lastname: Barak
authors.forename: Mary E
authors.initials: ME
authors.lastname: Abood
mesh_terms: 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
chemical_list: 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
references.citation: Nat Rev Drug Discov. 2004 Aug;3(8):673-83
references.pmid: 15286734
references.citation: FEBS Lett. 1991 Aug 19;288(1-2):17-20
references.pmid: 1652470
references.citation: J Biol Chem. 1998 Mar 13;273(11):6460-6
references.pmid: 9497379
references.citation: J Neurosci. 1985 Aug;5(8):2281-9
references.pmid: 2862229
references.citation: Biochem Biophys Res Commun. 2008 Jan 11;365(2):344-8
references.pmid: 17996730
references.citation: Br J Pharmacol. 2007 Nov;152(5):825-31
references.pmid: 17704827
references.citation: J Biol Chem. 2006 Aug 4;281(31):22021-22028
references.pmid: 16754668
references.citation: J Pharmacol Exp Ther. 2008 Jan;324(1):342-51
references.pmid: 17940199
references.citation: Cell Signal. 2003 May;15(5):463-9
references.pmid: 12639709
references.citation: Science. 2008 Sep 19;321(5896):1670-3
references.pmid: 18801996
references.citation: J Biol Chem. 1997 Oct 31;272(44):27497-500
references.pmid: 9346876
references.citation: Genomics. 1998 Jan 15;47(2):310-3
references.pmid: 9479505
references.citation: J Pharm Pharmacol. 1985 Dec;37(12):878-83
references.pmid: 2868095
references.citation: Cytometry A. 2005 May;65(1):69-76
references.pmid: 15778994
references.citation: Nature. 2007 Aug 9;448(7154):645-6
references.pmid: 17687303
references.citation: Assay Drug Dev Technol. 2003 Jun;1(3):409-24
references.pmid: 15090178
references.citation: Gut. 2006 May;55(5):681-8
references.pmid: 16299037
references.citation: J Biol Chem. 2004 Dec 10;279(50):51804-16
references.pmid: 15355987
references.citation: Biosci Biotechnol Biochem. 2002 Mar;66(3):679-81
references.pmid: 12005071
references.citation: FEBS Lett. 2006 Sep 18;580(21):5003-8
references.pmid: 16934253
references.citation: Science. 2005 Apr 22;308(5721):512-7
references.pmid: 15845844
references.citation: Br J Pharmacol. 2007 Dec;152(7):1092-101
references.pmid: 17876302
references.citation: J Pharmacol Exp Ther. 1987 Mar;240(3):890-4
references.pmid: 3031278
references.citation: Pharmacology. 2010;86(1):1-5
references.pmid: 20559017
references.citation: Cancer Sci. 2004 Feb;95(2):131-5
references.pmid: 14965362
references.citation: Mol Pharmacol. 1997 Feb;51(2):177-84
references.pmid: 9203621
references.citation: Clin Genet. 2004 Dec;66(6):537-44
references.pmid: 15521982
references.citation: Pharmacology. 2008;82(4):245-9
references.pmid: 18818509
references.citation: Nat Rev Drug Discov. 2008 Apr;7(4):339-57
references.pmid: 18382464
references.citation: Br J Pharmacol Chemother. 1964 Apr;22:246-53
references.pmid: 14190460
references.citation: Biochem Biophys Res Commun. 2010 Apr 30;395(2):232-7
references.pmid: 20361937