Functional Selectivity

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Recently, a novel theory called Functional Selectivity (also referred to in the literature as “agonist trafficking”, “biased agonism”, “differential engagement” and “protean agonism”) 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 (observed in systems with adequate constitutive activity) through a specific receptor subtype, and that this characteristic will be consistent with all effector 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. In fact, the literature suggests 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. 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.

[edit] References

Mailman 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.

Gay 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.

Mottola 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.

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

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