Functional selectivity (oragonist trafficking,biased agonism,biased signaling,ligand bias, anddifferential engagement) is theligand-dependent selectivity for certainsignal transduction pathways relative to a reference ligand (often the endogenous hormone or peptide) at the samereceptor.[1] Functional selectivity 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.[2] Functional selectivity, or biased signaling, is most extensively characterized atG protein coupled receptors (GPCRs).[3] A number of biased agonists, such as those atmuscarinic M2 receptors tested as analgesics[4] or antiproliferative drugs,[5] or those at opioid receptors that mediate pain,[6] show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies withG protein biased agonists at theμ-opioid receptor have shown equivalent efficacy for treating pain with reduced risk for addictive potential andrespiratory depression.[1][7] 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 receptorCXCR3 induced greaterchemotaxis of T cells relative to a G protein biased agonist.[8] Unlike a traditional balanced antagonist, a biased antagonist of the chemokine receptorCXCR4 that blocks G protein signaling while allowing beta-arrestin recruitment andendocytosis was shown to avoid tolerance.[9]
Functional selectivity has been proposed to broaden conventional definitions ofpharmacology.
Traditional pharmacologyposits that aligand can be either classified as anagonist (full or partial),antagonist or more recently aninverse agonist through a specific receptor subtype, and that this characteristic will be consistent with alleffector (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; such compounds may be termed asmixed 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.
These observations were made in a number of differentexpression systems, and therefore functional selectivity is not just anepiphenomenon of one particular expression system.
One notable example of functional selectivity occurs with the5-HT2A receptor, as well as the5-HT2C receptor.Serotonin, the main endogenous ligand of5-HT receptors, is a functionally selective agonist at this receptor, activatingphospholipase C (which leads toinositol triphosphate accumulation), but does not activatephospholipase A2, which would result inarachidonic acid signaling. However, the other endogenous compounddimethyltryptamine activates arachidonic acid signaling at the 5-HT2A receptor, as do many exogenous hallucinogens such asDOB andlysergic 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.[10]) Oligomers, specifically 5-HT2A–mGluR2Tooltip metabotropic glutamate receptor 2heteromers, mediate this effect. This may explain why some direct 5-HT2 receptor agonists havepsychedelic 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 mGluR2dimer, such aslisuride.[11]
Tianeptine, anatypical antidepressant, is thought to exhibit functional selectivity at theμ-opioid receptor to mediate its antidepressant effects.[12][13]
Oliceridine is a μ-opioid receptor agonist that has been described to be functionally selective towards G protein and away from β-arrestin2 pathways.[14] However, recent reports highlight that, rather than functional selectivity or 'G protein bias', this agonist has low intrinsic efficacy.[15]In vivo, it has been reported to mediate pain relief without tolerance nor gastrointestinal side effects.
Thedelta opioid receptor agonistsSNC80 andARM390 demonstrate functional selectivity that is thought to be due to their differing capacity to causereceptor internalization.[16] While SNC80 causes delta opioid receptors to internalize, ARM390 causes very little receptor internalization.[16] Functionally, that means that the effects of SNC80 (e.g.analgesia) do not occur when a subsequent dose follows the first, whereas the effects of ARM390 persist.[16] However, tolerance to ARM390's analgesia still occurs eventually after multiple doses, though through a mechanism that does not involve receptor internalization.[16] Interestingly, the other effects of ARM390 (e.g. decreased anxiety) persist after tolerance to its analgesic effects has occurred.[16]
An example of functional selectivity to bias metabolism was demonstrated for an electron transfer proteincytochrome P450 reductase (POR) with binding of small molecule ligands shown to alter the protein conformation and interaction with various redox partner proteins of POR.[17]
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