Many G-protein coupled receptors involved in pain and addiction are pharmacologically and biochemically well characterized, but some orphan receptors like GPR35 and GPR55, with homology to known receptors for drugs of abuse, remain poorly characterized. GPR55 is emerging as an important target in inflammatory pain, neuropathic pain, and bone development while other studies indicate that GPR55 activation is pro-carcinogenic. GPR55 does recognize certain cannabinoid ligands, so it has been suggested to be a third cannabinoid receptor. GPR35 is an important target in pain (spinal antinociception as well as inflammatory pain), heart disease, asthma, metabolic disease, inflammatory bowel disease and cancer. Each of these areas alone is medically important and each would benefit by the use of selective agonists and antagonists to further studies in their respective animal models. However, to date, no low nanomolar potency ligands have been discovered for these receptors nor is there a radioligand developed to characterize binding. The lack of such ligands is a critical barrier to progress in this field. The goal of this proposal is to leverage our recen promising high throughput, high content screening results for GPR55 agonists and GPR35 antagonists using structure based design and cheminformatics tools to develop an SAR for selected scaffolds that leads to the identification of low nanamolar ligands that retain high receptor selectivity.
We aim to discover nanomolar potency GPR55 and GPR35 ligands using a combination of structure-based design, molecular modeling, chemoinformatics, high-throughput screening and site directed mutagenesis.

Public Health Relevance

Many G-protein coupled receptors involved in pain and addiction are pharmacologically and biochemically well characterized, but some orphan receptors like GPR35 and GPR55, with homology to known receptors for drugs of abuse, remain poorly characterized. Both GPR55 and GPR35 are emerging as important targets in inflammatory pain, cancer and metabolic disease, to name a few. However, the lack of potent agonists and antagonists for these receptors are a critical barrier to progress this field. The goa of this proposal is to leverage our recent promising high throughput screening results for GPR55 agonists and GPR35 antagonists to develop such ligands.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA023204-08
Application #
8661145
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (58))
Program Officer
Hillery, Paul
Project Start
2007-06-15
Project End
2017-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
8
Fiscal Year
2014
Total Cost
$298,400
Indirect Cost
$63,600
Name
Temple University
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Howlett, Allyn C; Abood, Mary E (2017) CB1 and CB2 Receptor Pharmacology. Adv Pharmacol 80:169-206
Gherghina, Florin Liviu; Tica, Andrei Adrian; Deliu, Elena et al. (2017) Effects of VPAC1 activation in nucleus ambiguus neurons. Brain Res 1657:297-303
Brailoiu, G Cristina; Deliu, Elena; Barr, Jeffrey L et al. (2017) HIV Tat excites D1 receptor-like expressing neurons from rat nucleus accumbens. Drug Alcohol Depend 178:7-14
Fakhouri, Lara; Cook, Christopher D; Al-Huniti, Mohammed H et al. (2017) Design, synthesis and biological evaluation of GPR55 agonists. Bioorg Med Chem 25:4355-4367
Bertini, Simone; Chicca, Andrea; Gado, Francesca et al. (2017) Novel analogs of PSNCBAM-1 as allosteric modulators of cannabinoid CB1 receptor. Bioorg Med Chem 25:6427-6434
Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P et al. (2017) Structure-activity relationships of benzothiazole GPR35 antagonists. Bioorg Med Chem Lett 27:612-615
Lingerfelt, Mary A; Zhao, Pingwei; Sharir, Haleli P et al. (2017) Identification of Crucial Amino Acid Residues Involved in Agonist Signaling at the GPR55 Receptor. Biochemistry 56:473-486
Console-Bram, Linda; Ciuciu, Sandra M; Zhao, Pingwei et al. (2017) N-arachidonoyl glycine, another endogenous agonist of GPR55. Biochem Biophys Res Commun 490:1389-1393
Meza-AviƱa, Maria Elena; Lingerfelt, Mary A; Console-Bram, Linda M et al. (2016) Design, synthesis, and analysis of antagonists of GPR55: Piperidine-substituted 1,3,4-oxadiazol-2-ones. Bioorg Med Chem Lett 26:1827-1830
Gamage, Thomas F; Anderson, Johnathon C; Abood, Mary E (2016) CB1allosteric modulator Org27569 is an antagonist/inverse agonist of ERK1/2 signaling. Cannabis Cannabinoid Res 1:272-280

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