Presentation: 3B02

Concomitant with the increase in the number of GPCR targets is the recognition that GPCR responses to ligand binding can be complex, leading to identification of not only 'classical' agonists and antagonists but also inverse agonists and allosteric modulators. The variety of GPCR responses to ligand binding provides new opportunities for HTS. The challenge for HTS is to design effective and robust screens for the various types of ligands that modulate GPCR activity.

A review of high-throughput screens for agonists and positive allosteric modulators for two different GPCR’s will be presented. The development and validation of each screen required that the assay be sensitive enough to detect both agonists and potentiators in a single assay using a mixed-compound screening format. Small molecule agonists and potentiators were identified for a small molecule-activated GPCR. Although a small molecule agonist for a peptide-activated GPCR was not discovered, both peptide and small molecule potentiators were identified. Data for the development, validation, and screen will be presented for each assay.

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