Functional selectivity, ligand-directed trafficking, conformation-specific agonism: what's in a name?

Abstract

Research on the design of compounds to selectively affect specific subsets of signals downstream of receptors has burgeoned lately, and several reports discussed at Experimental Biology 2005 indicate progress is being made in the understanding of what makes a drug functionally selective. Different conformations adopted by receptors after associating with specific ligands can determine which intracellular signaling pathways get activated and which do not. The appeal of such specific compounds is enormous when one considers that many disease states might require the subtle manipulation of some (or even one) but not all downstream events stemming from specific receptor activation. Additionally, a better understanding of functional selectivity would likely improve the drug delivery process: if compounds are screened through several functional assays appropriately designed to look for compounds exhibiting a high degree of selectivity, then many potential lead compounds might not be as frequently overlooked.