The subject of this Phase II proposal is the completion of a GPCR screening panel for CNS- related receptors, enabling the discovery of therapeutic candidates acting at multiple GPCR targets. Most endogenous GPCR ligands activate multiple receptors. These ligands achieve biological efficacy through a "selective non-selectivity";whereby a small subset of receptors is activated to varying degrees by a specific ligand. Similarly, many effective drugs for neurological and substance abuse disorders are effective only because they modulate multiple targets. Unfortunately, current drug discovery technologies only permit ligand discovery one receptor at a time, effectively leaving any beneficial "off-target" receptor interactions to chance. In order to purposefully identify compounds that modulate multiple receptors of interest, a system is needed that profiles these responses simultaneously. In Phase I studies, Primity developed a novel GPCR assay and cellular barcoding system that enabled the simultaneous screening of eight GPCR targets in a single well of a microtiter plate. This Phase II proposal further expands the Neurological Disease Panel to 54 targets providing a global view of compound action across dozens of validated CNS drug targets. The techniques used for detecting GPCR activation will be optimized for high-throughput screening, and the data analysis automated, to enable screening of 4,000 wells (>100,000 data points) per screening day. The system will be benchmarked with a pilot screen of 1500 compounds to establish feasibility of massively parallel GPCR screening. The extension of targets to 54, coupled with the demonstration of the appropriate screening metrics outlined in this proposal, will provide the foundation for commercializing this technology as a novel screening platform for the purposeful discovery of pleiotropic ligands for neurological GPCR targets.
Neurological diseases involve a complex web of receptors with highly redundant functions making it difficult to achieve therapeutic efficacy using a traditional 'one drug, one receptor'model. The system described here facilitates highly efficient compound screening across a broad range of CNS- related targets to identify unexpected activities of known drugs and enable the discovery of drugs that simultaneously target multiple receptors.