Subtleties in GPCR drug discovery: a medicinal chemistry perspective

Therapeutic effects through G protein-coupled receptors (GPCRs) are promoted by a full agonist, partial agonist, neutral antagonist or inverse agonist. Dramatic change of function such as from a neutral antagonist to a full agonist with minimal variation of ligand structure is a phenomenon that medicinal chemists often encounter. This is also influenced by a change of assay format. The subtle nature of structure–function relationships is difficult to grasp unless carefully considered from both chemistry and assay perspectives. In this article we discuss the subtle aspects of GPCR drug discovery from the medicinal chemistry perspective.

► The subtlety of SAR in GPCR drug discovery was examined. ► Functional response can switch with minimal variation of ligand structure. ► Functional response is dependent on the assay format. ► Careful modification of structure is needed to develop SAR. ► Careful consideration of assay format is needed to classify compounds.