Functional selectivity

Source: Wikipedia, the free encyclopedia.

Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the

respiratory depression.[1][6] Studies within the chemokine receptor system also suggest that GPCR biased agonism is physiologically relevant. For example, a beta-arrestin biased agonist of the chemokine receptor CXCR3 induced greater chemotaxis of T cells relative to a G protein biased agonist.[7]

Functional vs. traditional selectivity

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

Traditional pharmacology

mixed agonist-antagonists
.

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

lysergic acid diethylamide (LSD). Notably, LSD does not activate IP3 signaling through this receptor to any significant extent. (Conversely, LSD, unlike serotonin, has negligible affinity for the 5-HT2C-VGV isoform, is unable to promote calcium release, and is, thus, functionally selective at 5-HT2C.[8]) Oligomers, specifically 5-HT2AmGluR2Tooltip metabotropic glutamate receptor 2 heteromers, mediate this effect. This may explain why some direct 5-HT2 receptor agonists have psychedelic effects, whereas compounds that indirectly increase serotonin signaling at the 5-HT2 receptors generally do not, for example: selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and medications using 5HT2A receptor agonists that do not have constitutive activity at the mGluR2 dimer, such as lisuride.[9]

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

analgesia) do not occur when a subsequent dose follows the first, whereas the effects of ARM390 persist.[14] However, tolerance to ARM390's analgesia still occurs eventually after multiple doses, though through a mechanism that does not involve receptor internalization.[14] Interestingly, the other effects of ARM390 (e.g. decreased anxiety) persist after tolerance to its analgesic effects has occurred.[14]

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