text: One notable example of functional selectivity occurs with the 5-HT receptor, as well as the 5-HT receptor. Serotonin, the main endogenous ligand of 5-HT receptors, is a functionally selective agonist at this receptor, activating phospholipase C (which leads to inositol triphosphate accumulation), but does not activate phospholipase A2, which would result in arachidonic acid signaling. However, the other endogenous compound dimethyltryptamine activates arachidonic acid signaling at the 5-HT receptor, as do many exogenous hallucinogens such as DOB and lysergic acid diethylamide (LSD). Notably, LSD does not activate IP signaling through this receptor to any significant extent. (Conversely, LSD, unlike serotonin, has negligible affinity for the 5-HT isoform, is unable to promote calcium release, and is, thus, functionally selective at 5-HT.) Oligomers, specifically 5-HT– heteromers, mediate this effect. This may explain why some direct 5-HT receptor agonists have psychedelic effects, whereas compounds that indirectly increase serotonin signaling at the 5-HT receptors generally do not, for example: selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), and medications using 5HT receptor agonists that do not have constitutive activity at the mGluR2 dimer, such as lisuride.
  Tianeptine, an atypical antidepressant, is thought to exhibit functional selectivity at the μ-opioid receptor to mediate its antidepressant effects.
  Oliceridine is a μ-opioid receptor agonist that has been described to be functionally selective towards G protein and away from β-arrestin2 pathways. However, recent reports highlight that, rather than functional selectivity or G protein bias, this agonist has low intrinsic efficacy. In vivo, it has been reported to mediate pain relief without tolerance nor gastrointestinal side effects.
  The delta opioid receptor agonists SNC80 and ARM390 demonstrate functional selectivity that is thought to be due to their differing capacity to cause receptor internalization. While SNC80 causes delta opioid receptors to internalize, ARM390 causes very little receptor internalization. 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. However, tolerance to ARM390's analgesia still occurs eventually after multiple doses, though through a mechanism that does not involve receptor internalization. Interestingly, the other effects of ARM390 (e.g. decreased anxiety) persist after tolerance to its analgesic effects has occurred.
  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.