G protein-coupled receptors (GPCRs) are members of the best known family of validated pharmaceutical research drug targets. More than 50% of approved drugs obtain their therapeutic effects by selectively targeting members of this family. Therefore, the pharmaceutical industry invests considerable resources into studying GPCR family members because they are justifiably perceived as sources of attractive therapeutic targets. Depending on targets and disease models, compounds that display agonist, antagonist, or allosteric properties can be sought.

Because the binding and signaling characteristics of GPCRs have been addressed elsewhere, this chapter will focus on current technologies available for investigating compounds that modulate the behavior of GPCRs. Indeed, over the last two decades high throughput screening (HTS) has become a very important tool in the discovery of lead compounds for all target classes including GPCRs. New technology developments have enabled screening to take great strides in recent years, evolving from high throughput to ultra-high throughput modes.

The competitive environment for the discovery of new drugs for disease targets necessitated the development of cost-effective and reliable high throughput screening strategies in order to accelerate the process of identifying lead compounds.1 Although the industry standard today is the use of 384-well plates, several pharmaceutical companies are developing 1536- or 3456-well-plate screens and screens without wells to increase their daily screening throughput.2-4 The applicability of GPCR assays to miniaturization will also be discussed throughout this chapter.

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