Small molecule probes for the orphan G-protein-coupled receptor GPR88

Research Triangle Institute, Durham NC

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Abstract

? DESCRIPTION (provided by applicant): 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.