The G-protein-coupled receptors constitute the largest class of transmembrane proteins in the human genome and play important roles in disease pathogenesis, yet many examples of orphan receptors with unknown endogenous ligands remain. The complex biology and potential for drug therapy within this class provide strong incentives for small molecule probe development to facilitate elucidation of mechanistic pathways and enable specific modulation of individual receptors. In this regard, our focus in this R21 application is to develop pharmacological tools for the recently discovered orphan receptor GPR88. GPR88 is richly expressed in both dopamine D1 and D2 receptor-expressing medium spiny neurons. Genetic knockout and gene expression studies have suggested that GPR88 plays an important role in the regulation of striatal functions and is implicated in the basal ganglia-associated disorders such as Parkinson's disease and schizophrenia. However, the biological functions of GPR88 are still largely unknown due to the lack of endogenous and synthetic potent, selective ligands. A detailed understanding of the mechanisms underlying agonist-induced GPR88 activation would facilitate drug (agonist/antagonist) discovery targeting this novel receptor. Unfortunately, potent GPR88 agonist tool compounds to selectively activate GPR88 are currently not available. In this application, we will focus primarily on the development of novel potent, selective GPR88 agonists using rational chemical synthesis, and virtual and biological screening. Once potent agonists are obtained, antagonists can be developed via structural modifications of an agonist scaffold as agonists and antagonists usually bind to the same pocket but different states of the receptors. However, due to the scope limitation of an R21 application, antagonist development is not encompassed in this proposal and will be addressed in the future R01 application.
GPR88 is an orphan G-protein-coupled receptor that has been implicated in mediation of dopaminergic activity and plays an important role in striatal functions. In this project, we propose to develop potent, selective GPR88 agonists, which will serve as pharmacological tools to study the GPR88 specific functions and its relevance to the basal ganglia-associated disorders such as Parkinson's disease, schizophrenia, bipolar disorder, and drug addiction.
| Jin, Chunyang; Decker, Ann M; Makhijani, Viren H et al. (2018) Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake. J Med Chem 61:6748-6758 |
| Decker, Ann M; Gay, Elaine A; Mathews, Kelly M et al. (2017) Development and validation of a high-throughput calcium mobilization assay for the orphan receptor GPR88. J Biomed Sci 24:23 |
| Jin, Chunyang; Decker, Ann M; Langston, Tiffany L (2017) Design, synthesis and pharmacological evaluation of 4-hydroxyphenylglycine and 4-hydroxyphenylglycinol derivatives as GPR88 agonists. Bioorg Med Chem 25:805-812 |
| Jin, Chunyang; Decker, Ann M; Harris, Danni L et al. (2016) Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies. ACS Chem Neurosci 7:1418-1432 |
