Functional selectivity
Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the
Functional vs. traditional selectivity
Functional selectivity has been proposed to broaden conventional definitions of pharmacology.
Traditional pharmacology
Functional selectivity posits that a ligand may inherently produce a mix of the classic characteristics through a single receptor isoform depending on the effector pathway coupled to that receptor. For instance, a ligand can not easily be classified as an agonist or antagonist, because it can be a little of both, depending on its preferred signal transduction pathways. Thus, such ligands must instead be classified on the basis of their individual effects in the cell, instead of being either an agonist or antagonist to a receptor.
It is also important to note that these observations were made in a number of different expression systems and therefore functional selectivity is not just an epiphenomenon of one particular expression system.
Examples
One notable example of functional selectivity occurs with the
Tianeptine, an atypical antidepressant, is thought to exhibit functional selectivity at the μ-opioid receptor to mediate its antidepressant effects.[10][11]
Oliceridine is a μ-opioid receptor agonist that has been described to be functionally selective towards G protein and away from β-arrestin2 pathways.[12] However, recent reports highlight that, rather than functional selectivity or 'G protein bias', this agonist has low intrinsic efficacy.[13] In vivo, it has been reported to mediate pain relief without tolerance nor gastrointestinal side effects.
The
An example of functional selectivity to bias metabolism was demonstrated for an electron transfer protein cytochrome P450 reductase (POR) with binding of small molecule ligands shown to alter the protein conformation and interaction with various redox partner proteins of POR.[15]
See also
References
Further reading
This article includes a list of general references, but it lacks sufficient corresponding inline citations. (November 2013) |
- Tan L, Yan W, McCorvy JD, Cheng J (July 2018). "Biased Ligands of G Protein-Coupled Receptors: Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential". J. Med. Chem. 61 (22): 9841–9878. S2CID 49414225.
- Costa-Neto CM, Parreiras-E-Silva LT, Bouvier M (2016). "A Pluridimensional View of Biased Agonism". Mol. Pharmacol. 90 (5): 587–595. PMID 27638872.
- Gesty-Palmer D, Luttrell LM (2011). "Refining Efficacy: Exploiting Functional Selectivity for Drug Discovery". Pharmacology of G Protein Coupled Receptors. Advances in Pharmacology. Vol. 62. pp. 79–107. PMID 21907907.
- DeWire SM, Violin JD (July 2011). "Biased ligands for better cardiovascular drugs: dissecting G-protein-coupled receptor pharmacology". Circ. Res. 109 (2): 205–16. PMID 21737816.
- Kenakin T (1995). "Agonist-Receptor Efficacy. II. Agonist Trafficking of Receptor Signals". Trends Pharmacol Sci. 16 (7): 232–8. PMID 7667897.