Functional selectivity

Functional selectivity (or “agonist trafficking”, “biased agonism”, “differential engagement” and “protean agonism”) is the ligand-dependent selectivity for certain signal transduction pathways in one and the same receptor. This can be present when a receptor has several possible signal transduction pathways. To which degree each pathway is activated thus depends on which ligand binds to the receptor ^[1].

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Functional vs. traditional selectivity

Functional selectivity has been proposed to broaden conventional definitions of pharmacology.

Traditional pharmacology posits that a ligand can be either classified as an agonist (full or partial), antagonist or more recently an inverse agonist through a specific receptor subtype, and that this characteristic will be consistent with all effector (second messenger) systems coupled to that receptor. While this dogma has been the backbone of ligand-receptor interactions for decades now, more recent data indicates that this classic definition of ligand-protein associations does not hold true for a number of compounds.

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.

See also

Signal transduction

References

Urban JD et al. (2007). "Functional selectivity and classical concepts of quantitative pharmacology". J Pharmacol Exp Ther 320: 1-13. PMID 16803859.

Mailman RB et al. (2004). "Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland". Med Chem Res 13: 115-126.

Nelson CP et al. (2004). "Functional selectivity of muscarinic receptor antagonists for inhibition of M3-mediated phosphoinositide responses in guinea pig urinary bladder and submandibular salivary gland". J Pharmacol Exp Ther. 310: 1255-65. PMID 15140916. Fulltext

Gay EA et al. (2004). "Functional selectivity of D2 receptor ligands in a Chinese hamster ovary hD2L cell line: evidence for induction of ligand-specific receptor states". Mol Pharmacol 66: 97-105. PMID 15213300. Fulltext

Mottola DM et al. (2002). "Functional Selectivity of Dopamine Receptors Agonists. I. Selective Activation of Postsynaptic Dopamine D2 Receptors Linked to Adenylate Cyclase". J Pharmacol Exp Ther. 301: 1166-1178. PMID 12023552. Fulltext

Lawler CP et al. (1999). "Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes". Neuropsychopharmacology 20: 612-27. PMID 10327430. Fulltext

Kenakin T (1995). "Agonist-Receptor Efficacy. II. Agonist Trafficking of Receptor Signals". Trends Pharmacol Sci 16: 232-238. PMID 7667897.