Chemical Deorphaning of GPR88: A Candidate Modulator of Motor Function

Dopamine replacement therapy for Parkinson's disease activates neurons in a particular region of the brain, the striatum, leading to an improvement in disease symptoms. This action occurs through a dopamine receptor - best thought of as a 'lock' that the dopamine 'key' fits in. In the striatum, there is another receptor that has been recently discovered and is selectively expressed in this region (i.e. is not found in other tissues). However, the 'key' to turn on this new receptor is not yet known (in pharmacological terms, the corresponding receptor is therefore referred to as an 'orphan'). We want to explore whether activating this receptor will improve the symptoms of Parkinson's disease. The first step in this process is to find a 'key' that fits. To accomplish this, we will utilize a highly sensitive assay that we developed in our laboratory. We will work in collaboration with the Harvard Center for Neurdegeneration and Repair to screen a large collection (>100,000) of candidate compounds to define a molecule that fits the orphan receptor.