Functional selectivity – chance for better and safer drugs?

Purpose: The article reviews the current state of knowledge about functional selectivity (biased agonism) at G protein-coupled receptors (GPCRs), with a particular focus on serotonin 5-HT_1A receptors.

Views: Recently, functional selectivity has been one of the fastest growing topics in GPCRs pharmacology. Research on this phenomenon allowed identification of signal transduction pathways which can be preferentially targeted to achieve improved therapeutic effects or, conversely, which are associated with adverse effects. Oliceridine, a phase III clinical candidate for treatment of pain, is an example of a functionally selective ligand of µ-opioid receptors that preferentially activates signal transduction via G proteins rather than β-arrestin. Biased agonism, or the ability to preferentially activate specific signalling pathways, has been identified for many therapeutically important GPCRs, such as µ-opioid receptors, α_1- and β₂-adrenoceptors, dopamine D2_L and D₁ receptors, angiotensin 1A receptor, as well as 5-HT₂ and 5-HT_1A serotonin receptors. The recently discovered compounds F15599 and F13714 have been identified as functionally and regionally selective ligands of 5-HT_1A receptors. These compounds constitute a new generation of pharmacological tools with high therapeutic potential, which is currently being investigated for the treatment of disorders including Parkinson’s disease, depression and Rett syndrome.

Conclusions: Functional selectivity (biased agonism) enables separation of the therapeutic effect from the adverse effects, so far considered to be intrinsically linked to the mechanism of action, by preferentially targeting signal transduction pathways associated with beneficial effects. It may therefore offer new opportunities for improved development of more effective and safer drugs.