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Activation of GPR88 by a Small Molecular Weight Compound: Screening for Drug-like Modulators of GPR88 Function

The expression pattern of GPR88 within the brain suggests a role for this receptor in the control of motor function.  The natural binding partner for GPR88 is not known. However, using a cell-based assay system we identified a compound that was able to stimulate receptor activity. We now have the opportunity to screen for further activators and inhibitors of GPR88 to help us understand the biology of this receptor and its relevance to Parkinson’s disease.

Project Description: 
Using an assay that allows us to specifically monitor the activity of GPR88 expressed in a cell line, we have identified a molecule that is able to stimulate the activity of GPR88.  The assay technology is robust and suitable for high-throughput drug discovery. This will allow us to screen for ‘drug-like’ molecules that show activity against GPR88 using a diverse collection of 100,000 high-quality chemical compounds. We will configure the assay to be able to search for inhibitors of GPR88 activity and also other molecules that are able to stimulate GPR88 activity. 

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
The distinct localization of GPR88 within the striatum is of great potential interest with respect to the study of Parkinson’s disease.  Research has already suggested an interaction between GPR88 and the striatal dopaminergic system.  The ability to manipulate this receptor experimentally may help our understanding of GPR88 in normal brain function and ultimately lead to drug discovery programmes for therapeutic intervention in Parkinson’s disease.

Anticipated Outcome: 
We have a starting point where we can switch this receptor on and detect its activity. High-throughput screening technology can now be applied to identify further compounds that modulate GPR88 function. By initially generating research tools, we hope to further our understanding of GPR88 biology and hopefully provide a basis for targeted drug discovery in Parkinson’s disease.

Progress Report

We had observed that the PD related neurotoxin rotenone was able to promote a novel aspect of GPR88 signaling.  A high-throughput screening assay was developed to search our chemical library for compounds that would inhibit the activity of rotenone at GPR88.  We were able to identify compounds that blocked the stimulatory activity of rotenone and additionally we identified novel compounds, unrelated to rotenone, that were themselves able to stimulate GPR88.  Screening hits were triaged to evaluate potency and selectivity and to gain a preliminary insight into their pharmacological mode of action. Medicinal chemistry evaluation identified chemotypes with attributes amenable to further hit to lead progression.  These reagents may help as research tools in order to further our understanding of this orphan CNS receptor and ultimately may support the development of drugs intended for PD treatment.

April 2012


  • Craig Southern, PhD

    London United Kingdom

  • Deborah Taylor, PhD

    London United Kingdom

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