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Functional selectivity

May 03, 2024

Not to be confused with binding selectivity.

Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a reference ligand (often the endogenous hormone or peptide) at the same receptor.[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 at G protein coupled receptors (GPCRs).[3] A number of biased agonists, such as those at muscarinic M2 receptors tested as analgesics[4] or antiproliferative drugs,[5] or those at opioid receptors that mediate pain, show potential at various receptor families to increase beneficial properties while reducing side effects. For example, pre-clinical studies with G protein biased agonists at the μ-opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and 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 edit

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; such compounds may be termed as 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 edit

One notable example of functional selectivity occurs with the 5-HT2A receptor, as well as the 5-HT2C 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-HT2A receptor, as do many exogenous hallucinogens such as DOB and 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-HT2A–mGluR2Tooltip 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 delta opioid receptor agonists SNC80 and ARM390 demonstrate functional selectivity that is thought to be due to their differing capacity to cause receptor internalization.[14] While SNC80 causes delta opioid receptors to internalize, ARM390 causes very little receptor internalization.[14] 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.[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 edit

References edit

  1. ^ a b Smith, Jeffrey S.; Lefkowitz, Robert J.; Rajagopal, Sudarshan (2018-01-05). "Biased signalling: from simple switches to allosteric microprocessors". Nature Reviews. Drug Discovery. 17 (4): 243–260. doi:10.1038/nrd.2017.229. ISSN 1474-1784. PMC 5936084. PMID 29302067.
  2. ^ Simmons MA (June 2005). "Functional selectivity, ligand-directed trafficking, conformation-specific agonism: what's in a name?". Mol. Interv. 5 (3): 154–7. doi:10.1124/mi.5.3.4. PMID 15994454.
  3. ^ Bock, Andreas; Merten, Nicole; Schrage, Ramona; Dallanoce, Clelia; Bätz, Julia; Klöckner, Jessica; Schmitz, Jens; Matera, Carlo; Simon, Katharina; Kebig, Anna; Peters, Lucas; Müller, Anke; Schrobang-Ley, Jasmin; Tränkle, Christian; Hoffmann, Carsten; De Amici, Marco; Holzgrabe, Ulrike; Kostenis, Evi; Mohr, Klaus (2012). "The allosteric vestibule of a seven transmembrane helical receptor controls G-protein coupling". Nature Communications. 3 (1): 1044. Bibcode:2012NatCo...3.1044B. doi:10.1038/ncomms2028. ISSN 2041-1723. PMC 3658004. PMID 22948826.
  4. ^ Matera, Carlo; Flammini, Lisa; Quadri, Marta; Vivo, Valentina; Ballabeni, Vigilio; Holzgrabe, Ulrike; Mohr, Klaus; De Amici, Marco; Barocelli, Elisabetta; Bertoni, Simona; Dallanoce, Clelia (2014). "Bis(ammonio)alkane-type agonists of muscarinic acetylcholine receptors: Synthesis, in vitro functional characterization, and in vivo evaluation of their analgesic activity". European Journal of Medicinal Chemistry. 75: 222–232. doi:10.1016/j.ejmech.2014.01.032. ISSN 0223-5234. PMID 24534538.
  5. ^ Cristofaro, Ilaria; Spinello, Zaira; Matera, Carlo; Fiore, Mario; Conti, Luciano; De Amici, Marco; Dallanoce, Clelia; Tata, Ada Maria (2018). "Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells". Neurochemistry International. 118: 52–60. doi:10.1016/j.neuint.2018.04.010. ISSN 0197-0186. PMID 29702145. S2CID 207125517.
  6. ^ Manglik, Aashish; Lin, Henry; Aryal, Dipendra K.; McCorvy, John D.; Dengler, Daniela; Corder, Gregory; Levit, Anat; Kling, Ralf C.; Bernat, Viachaslau (8 September 2016). "Structure-based discovery of opioid analgesics with reduced side effects". Nature. 537 (7619): 185–190. Bibcode:2016Natur.537..185M. doi:10.1038/nature19112. ISSN 1476-4687. PMC 5161585. PMID 27533032.
  7. ^ Smith, Jeffrey S.; Nicholson, Lowell T.; Suwanpradid, Jutamas; Glenn, Rachel A.; Knape, Nicole M.; Alagesan, Priya; Gundry, Jaimee N.; Wehrman, Thomas S.; Atwater, Amber Reck (2018-11-06). "Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation". Science Signaling. 11 (555): eaaq1075. doi:10.1126/scisignal.aaq1075. ISSN 1937-9145. PMC 6329291. PMID 30401786.
  8. ^ Backstrom, Jon R; Chang, Mike S; Chu, Hsin; Niswender, Colleen M; Sanders-Bush, Elaine (Aug 1, 1999). "Agonist-Directed Signaling of Serotonin 5-HT2C Receptors: Differences Between Serotonin and Lysergic Acid Diethylamide (LSD)". Neuropsychopharmacology. 21 (2): 77–81. doi:10.1016/S0893-133X(99)00005-6. PMID 10432492. S2CID 25007217.
  9. ^ Urban JD, Clarke WP, von Zastrow M, Nichols DE, Kobilka B, Weinstein H, Javitch JA, Roth BL, Christopoulos A, Sexton PM, Miller KJ, Spedding M, Mailman RB (January 2007). "Functional selectivity and classical concepts of quantitative pharmacology". J. Pharmacol. Exp. Ther. 320 (1): 1–13. doi:10.1124/jpet.106.104463. PMID 16803859. S2CID 447937.
  10. ^ Samuels BA, Nautiyal KM, Kruegel AC, Levinstein MR, Magalong VM, Gassaway MM, Grinnell SG, Han J, Ansonoff MA, Pintar JE, Javitch JA, Sames D, Hen R (2017). "The Behavioral Effects of the Antidepressant Tianeptine Require the Mu Opioid Receptor". Neuropsychopharmacology. 42 (10): 2052–2063. doi:10.1038/npp.2017.60. PMC 5561344. PMID 28303899.
  11. ^ Cavalla, D; Chianelli, F (August 2015). "Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats". European Journal of Pharmacology. 761: 268–272. doi:10.1016/j.ejphar.2015.05.067. PMID 26068549.
  12. ^ DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD (March 2013). "A G protein-biased ligand at the μ-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine". Journal of Pharmacology and Experimental Therapeutics. 344 (3): 708–17. doi:10.1124/jpet.112.201616. PMID 23300227. S2CID 8785003.
  13. ^ Gillis, A; Gondin, AB; Kliewer, A; Sanchez, J; Lim, HD; Alamein, C; Manandhar, P; Santiago, M; Fritzwanker, S; Schmiedel, F; Katte, TA; Reekie, T; Grimsey, NL; Kassiou, M; Kellam, B; Krasel, C; Halls, ML; Connor, M; Lane, JR; Schulz, S; Christie, MJ; Canals, M (31 March 2020). "Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists". Science Signaling. 13 (625): eaaz3140. doi:10.1126/scisignal.aaz3140. PMID 32234959. S2CID 214771721.
  14. ^ a b c d e Pradhan, Amynah A.; Befort, Katia; Nozaki, Chihiro; Gavériaux-Ruff, Claire; Kieffer, Brigitte L. (October 2011). "The delta opioid receptor: an evolving target for the treatment of brain disorders". Trends in Pharmacological Sciences. 32 (10): 581–590. doi:10.1016/j.tips.2011.06.008. PMC 3197801. PMID 21925742.
  15. ^ Jensen, Simon Bo; Thodberg, Sara; Parween, Shaheena; Moses, Matias E.; Hansen, Cecilie C.; Thomsen, Johannes; Sletfjerding, Magnus B.; Knudsen, Camilla; Del Giudice, Rita; Lund, Philip M.; Castaño, Patricia R. (December 2021). "Biased cytochrome P450-mediated metabolism via small-molecule ligands binding P450 oxidoreductase". Nature Communications. 12 (1): 2260. Bibcode:2021NatCo..12.2260J. doi:10.1038/s41467-021-22562-w. ISSN 2041-1723. PMC 8050233. PMID 33859207.

Further reading edit

  • Tan L, Yan W, McCorvy JD, Cheng J (July 2018). "Biased Ligands of G Protein-Coupled Receptors: Structure-Functional Selectivity Relationships (SFSRs) and Therapeutic Potential". J. Med. Chem. 61 (22): 9841–9878. doi:10.1021/acs.jmedchem.8b00435. PMID 29939744. S2CID 49414225.
  • Costa-Neto CM, Parreiras-E-Silva LT, Bouvier M (2016). "A Pluridimensional View of Biased Agonism". Mol. Pharmacol. 90 (5): 587–595. doi:10.1124/mol.116.105940. PMID 27638872.
  • Gesty-Palmer D, Luttrell LM (2011). "Refining Efficacy: Exploiting Functional Selectivity for Drug Discovery". Pharmacology of G Protein Coupled Receptors. Advances in Pharmacology. Vol. 62. pp. 79–107. doi:10.1016/B978-0-12-385952-5.00009-9. ISBN 9780123859525. PMID 21907907.
  • DeWire SM, Violin JD (July 2011). "Biased ligands for better cardiovascular drugs: dissecting G-protein-coupled receptor pharmacology". Circ. Res. 109 (2): 205–16. doi:10.1161/CIRCRESAHA.110.231308. PMID 21737816.
  • Kenakin T (1995). "Agonist-Receptor Efficacy. II. Agonist Trafficking of Receptor Signals". Trends Pharmacol Sci. 16 (7): 232–8. doi:10.1016/S0165-6147(00)89032-X. PMID 7667897.


May 03, 2024
functional, selectivity, confused, with, binding, selectivity, agonist, trafficking, biased, agonism, biased, signaling, ligand, bias, differential, engagement, ligand, dependent, selectivity, certain, signal, transduction, pathways, relative, reference, ligan. Not to be confused with binding selectivity Functional selectivity or agonist trafficking biased agonism biased signaling ligand bias and differential engagement is the ligand dependent selectivity for certain signal transduction pathways relative to a reference ligand often the endogenous hormone or peptide at the same receptor 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 at G protein coupled receptors GPCRs 3 A number of biased agonists such as those at muscarinic M2 receptors tested as analgesics 4 or antiproliferative drugs 5 or those at opioid receptors that mediate pain show potential at various receptor families to increase beneficial properties while reducing side effects For example pre clinical studies with G protein biased agonists at the m opioid receptor show equivalent efficacy for treating pain with reduced risk for addictive potential and 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 Contents 1 Functional vs traditional selectivity 2 Examples 3 See also 4 References 5 Further readingFunctional vs traditional selectivity editFunctional 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 such compounds may be termed as 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 editOne notable example of functional selectivity occurs with the 5 HT2A receptor as well as the 5 HT2C 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 HT2A receptor as do many exogenous hallucinogens such as DOB and 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 HT2A mGluR2Tooltip 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 m opioid receptor to mediate its antidepressant effects 10 11 Oliceridine is a m opioid receptor agonist that has been described to be functionally selective towards G protein and away from b 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 delta opioid receptor agonists SNC80 and ARM390 demonstrate functional selectivity that is thought to be due to their differing capacity to cause receptor internalization 14 While SNC80 causes delta opioid receptors to internalize ARM390 causes very little receptor internalization 14 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 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 editSignal transduction Second messenger systemReferences edit a b Smith Jeffrey S Lefkowitz Robert J Rajagopal Sudarshan 2018 01 05 Biased signalling from simple switches to allosteric microprocessors Nature Reviews Drug Discovery 17 4 243 260 doi 10 1038 nrd 2017 229 ISSN 1474 1784 PMC 5936084 PMID 29302067 Simmons MA June 2005 Functional selectivity ligand directed trafficking conformation specific agonism what s in a name Mol Interv 5 3 154 7 doi 10 1124 mi 5 3 4 PMID 15994454 Bock Andreas Merten Nicole Schrage Ramona Dallanoce Clelia Batz Julia Klockner Jessica Schmitz Jens Matera Carlo Simon Katharina Kebig Anna Peters Lucas Muller Anke Schrobang Ley Jasmin Trankle Christian Hoffmann Carsten De Amici Marco Holzgrabe Ulrike Kostenis Evi Mohr Klaus 2012 The allosteric vestibule of a seven transmembrane helical receptor controls G protein coupling Nature Communications 3 1 1044 Bibcode 2012NatCo 3 1044B doi 10 1038 ncomms2028 ISSN 2041 1723 PMC 3658004 PMID 22948826 Matera Carlo Flammini Lisa Quadri Marta Vivo Valentina Ballabeni Vigilio Holzgrabe Ulrike Mohr Klaus De Amici Marco Barocelli Elisabetta Bertoni Simona Dallanoce Clelia 2014 Bis ammonio alkane type agonists of muscarinic acetylcholine receptors Synthesis in vitro functional characterization and in vivo evaluation of their analgesic activity European Journal of Medicinal Chemistry 75 222 232 doi 10 1016 j ejmech 2014 01 032 ISSN 0223 5234 PMID 24534538 Cristofaro Ilaria Spinello Zaira Matera Carlo Fiore Mario Conti Luciano De Amici Marco Dallanoce Clelia Tata Ada Maria 2018 Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells Neurochemistry International 118 52 60 doi 10 1016 j neuint 2018 04 010 ISSN 0197 0186 PMID 29702145 S2CID 207125517 Manglik Aashish Lin Henry Aryal Dipendra K McCorvy John D Dengler Daniela Corder Gregory Levit Anat Kling Ralf C Bernat Viachaslau 8 September 2016 Structure based discovery of opioid analgesics with reduced side effects Nature 537 7619 185 190 Bibcode 2016Natur 537 185M doi 10 1038 nature19112 ISSN 1476 4687 PMC 5161585 PMID 27533032 Smith Jeffrey S Nicholson Lowell T Suwanpradid Jutamas Glenn Rachel A Knape Nicole M Alagesan Priya Gundry Jaimee N Wehrman Thomas S Atwater Amber Reck 2018 11 06 Biased agonists of the chemokine receptor CXCR3 differentially control chemotaxis and inflammation Science Signaling 11 555 eaaq1075 doi 10 1126 scisignal aaq1075 ISSN 1937 9145 PMC 6329291 PMID 30401786 Backstrom Jon R Chang Mike S Chu Hsin Niswender Colleen M Sanders Bush Elaine Aug 1 1999 Agonist Directed Signaling of Serotonin 5 HT2C Receptors Differences Between Serotonin and Lysergic Acid Diethylamide LSD Neuropsychopharmacology 21 2 77 81 doi 10 1016 S0893 133X 99 00005 6 PMID 10432492 S2CID 25007217 Urban JD Clarke WP von Zastrow M Nichols DE Kobilka B Weinstein H Javitch JA Roth BL Christopoulos A Sexton PM Miller KJ Spedding M Mailman RB January 2007 Functional selectivity and classical concepts of quantitative pharmacology J Pharmacol Exp Ther 320 1 1 13 doi 10 1124 jpet 106 104463 PMID 16803859 S2CID 447937 Samuels BA Nautiyal KM Kruegel AC Levinstein MR Magalong VM Gassaway MM Grinnell SG Han J Ansonoff MA Pintar JE Javitch JA Sames D Hen R 2017 The Behavioral Effects of the Antidepressant Tianeptine Require the Mu Opioid Receptor Neuropsychopharmacology 42 10 2052 2063 doi 10 1038 npp 2017 60 PMC 5561344 PMID 28303899 Cavalla D Chianelli F August 2015 Tianeptine prevents respiratory depression without affecting analgesic effect of opiates in conscious rats European Journal of Pharmacology 761 268 272 doi 10 1016 j ejphar 2015 05 067 PMID 26068549 DeWire SM Yamashita DS Rominger DH Liu G Cowan CL Graczyk TM Chen XT Pitis PM Gotchev D Yuan C Koblish M Lark MW Violin JD March 2013 A G protein biased ligand at the m opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine Journal of Pharmacology and Experimental Therapeutics 344 3 708 17 doi 10 1124 jpet 112 201616 PMID 23300227 S2CID 8785003 Gillis A Gondin AB Kliewer A Sanchez J Lim HD Alamein C Manandhar P Santiago M Fritzwanker S Schmiedel F Katte TA Reekie T Grimsey NL Kassiou M Kellam B Krasel C Halls ML Connor M Lane JR Schulz S Christie MJ Canals M 31 March 2020 Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists Science Signaling 13 625 eaaz3140 doi 10 1126 scisignal aaz3140 PMID 32234959 S2CID 214771721 a b c d e Pradhan Amynah A Befort Katia Nozaki Chihiro Gaveriaux Ruff Claire Kieffer Brigitte L October 2011 The delta opioid receptor an evolving target for the treatment of brain disorders Trends in Pharmacological Sciences 32 10 581 590 doi 10 1016 j tips 2011 06 008 PMC 3197801 PMID 21925742 Jensen Simon Bo Thodberg Sara Parween Shaheena Moses Matias E Hansen Cecilie C Thomsen Johannes Sletfjerding Magnus B Knudsen Camilla Del Giudice Rita Lund Philip M Castano Patricia R December 2021 Biased cytochrome P450 mediated metabolism via small molecule ligands binding P450 oxidoreductase Nature Communications 12 1 2260 Bibcode 2021NatCo 12 2260J doi 10 1038 s41467 021 22562 w ISSN 2041 1723 PMC 8050233 PMID 33859207 Further reading editThis article includes a list of general references but it lacks sufficient corresponding inline citations Please help to improve this article by introducing more precise citations November 2013 Learn how and when to remove this message Tan L Yan W McCorvy JD Cheng J July 2018 Biased Ligands of G Protein Coupled Receptors Structure Functional Selectivity Relationships SFSRs and Therapeutic Potential J Med Chem 61 22 9841 9878 doi 10 1021 acs jmedchem 8b00435 PMID 29939744 S2CID 49414225 Costa Neto CM Parreiras E Silva LT Bouvier M 2016 A Pluridimensional View of Biased Agonism Mol Pharmacol 90 5 587 595 doi 10 1124 mol 116 105940 PMID 27638872 Gesty Palmer D Luttrell LM 2011 Refining Efficacy Exploiting Functional Selectivity for Drug Discovery Pharmacology of G Protein Coupled Receptors Advances in Pharmacology Vol 62 pp 79 107 doi 10 1016 B978 0 12 385952 5 00009 9 ISBN 9780123859525 PMID 21907907 DeWire SM Violin JD July 2011 Biased ligands for better cardiovascular drugs dissecting G protein coupled receptor pharmacology Circ Res 109 2 205 16 doi 10 1161 CIRCRESAHA 110 231308 PMID 21737816 Kenakin T 1995 Agonist Receptor Efficacy II Agonist Trafficking of Receptor Signals Trends Pharmacol Sci 16 7 232 8 doi 10 1016 S0165 6147 00 89032 X PMID 7667897 Retrieved from https en wikipedia org w index php title Functional selectivity amp oldid 1217610678, wikipedia, wiki, book, books, library,

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