Drug addiction continues to remain a major public health concern in the United States. Addictive behavior results from changes in central nervous system signaling pathways that are modified after exposure to drugs of abuse. In particular, compounds such as cannabinoids and opiates that influence mood and pain perception are commonly associated with addictive behaviors. Many receptors regulating addiction are pharmacologically and biochemically well characterized, but some orphan receptors like GPR35 with homology to known receptors of abuse remain almost totally uncharacterized. The identification of small molecules capable of selectively inhibiting or activating orphans will provide enabling tools for elucidating novel molecular pathways underlying addictive behaviors. This proposal seeks to provide new compounds for characterizing the orphan G protein-coupled receptor GPR35. We have identified pamoic acid analogs as potent GPR35 agonists using in vitro assays and have found that pamoic acid induces antinociception. We propose a strategy to identify predominantly commercially available small molecules towards the objective of identifying a useful molecular probe for GPR35. Optimizing these novel compounds will allow the characterization of GPR35 biology in vitro and in animal models of pain. Our results suggest unexpected biological functions of pamoic acid and potential application for new drug development.

Public Health Relevance

This proposal will provide tools for delineating the pharmacology of GPR35, potentially provide compounds for targeted therapeutics of pathways underlying pain, and clarify our understanding of GPR35 biology in vitro and in animal models of pain.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DA029432-02
Application #
7935205
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (50))
Program Officer
Singh, Hari
Project Start
2009-09-30
Project End
2012-02-28
Budget Start
2010-09-01
Budget End
2012-02-28
Support Year
2
Fiscal Year
2010
Total Cost
$202,046
Indirect Cost
Name
Temple University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Kotsikorou, Evangelia; Sharir, Haleli; Shore, Derek M et al. (2013) Identification of the GPR55 antagonist binding site using a novel set of high-potency GPR55 selective ligands. Biochemistry 52:9456-69
Kotsikorou, Evangelia; Madrigal, Karla E; Hurst, Dow P et al. (2011) Identification of the GPR55 agonist binding site using a novel set of high-potency GPR55 selective ligands. Biochemistry 50:5633-47
Zhao, Pingwei; Sharir, Haleli; Kapur, Ankur et al. (2010) Targeting of the orphan receptor GPR35 by pamoic acid: a potent activator of extracellular signal-regulated kinase and ?-arrestin2 with antinociceptive activity. Mol Pharmacol 78:560-8