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Biased Ligands of G Protein-Coupled Receptors (GPCRs): Structure–Functional Selectivity Relationships (SFSRs) and Therapeutic Potential

  • Liang Tan
    Liang Tan
    iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong District, Shanghai 201210, China
    More by Liang Tan
  • Wenzhong Yan
    Wenzhong Yan
    iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong District, Shanghai 201210, China
    More by Wenzhong Yan
  • John D. McCorvy*
    John D. McCorvy
    Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 W. Watertown Plank Road, Milwaukee, Wisconsin 53226, United States
    *J.D.M.: phone, +1 414-955-7635; e-mail, [email protected]
  • , and 
  • Jianjun Cheng*
    Jianjun Cheng
    iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Pudong District, Shanghai 201210, China
    *J.C.: phone, +86 21 20685237; e-mail, [email protected]
Cite this: J. Med. Chem. 2018, 61, 22, 9841–9878
Publication Date (Web):June 25, 2018
https://doi.org/10.1021/acs.jmedchem.8b00435
Copyright © 2018 American Chemical Society

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    Abstract

    Abstract Image

    G protein-coupled receptors (GPCRs) signal through both G-protein-dependent and G-protein-independent pathways, and β-arrestin recruitment is the most recognized one of the latter. Biased ligands selective for either pathway are expected to regulate biological functions of GPCRs in a more precise way, therefore providing new drug molecules with superior efficacy and/or reduced side effects. During the past decade, biased ligands have been discovered and developed for many GPCRs, such as the μ opioid receptor, the angiotensin II receptor type 1, the dopamine D2 receptor, and many others. In this Perspective, recent advances in this field are reviewed by discussing the structure–functional selectivity relationships (SFSRs) of GPCR biased ligands and the therapeutic potential of these molecules. Further understanding of the biological functions associated with each signaling pathway and structural basis for biased signaling will facilitate future drug design in this field.

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    14. Salvatore Pacifico, Federica Ferrari, Valentina Albanese, Erika Marzola, Joaquim Azevedo Neto, Chiara Ruzza, Girolamo Calò, Delia Preti, Remo Guerrini. Biased Agonism at Nociceptin/Orphanin FQ Receptors: A Structure Activity Study on N/OFQ(1–13)-NH2. Journal of Medicinal Chemistry 2020, 63 (19) , 10782-10795. https://doi.org/10.1021/acs.jmedchem.9b02057
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    17. Bingjie Zhang, Simeng Zhao, Dehua Yang, Yiran Wu, Ye Xin, Haijie Cao, Xi-Ping Huang, Xiaoqing Cai, Wen Sun, Na Ye, Yueming Xu, Yao Peng, Suwen Zhao, Zhi-Jie Liu, Guisheng Zhong, Ming-Wei Wang, Wenqing Shui. A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts. ACS Central Science 2020, 6 (2) , 213-225. https://doi.org/10.1021/acscentsci.9b01125
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    20. Michael L. Martini, Jing Liu, Caroline Ray, Xufen Yu, Xi-Ping Huang, Aarti Urs, Nikhil Urs, John D. McCorvy, Marc G. Caron, Bryan L. Roth, Jian Jin. Defining Structure–Functional Selectivity Relationships (SFSR) for a Class of Non-Catechol Dopamine D1 Receptor Agonists. Journal of Medicinal Chemistry 2019, 62 (7) , 3753-3772. https://doi.org/10.1021/acs.jmedchem.9b00351
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    23. Kihang Choi. The Structure-property Relationships of GPCR-targeted Drugs Approved between 2011 and 2021. Current Medicinal Chemistry 2023, 30 (31) , 3527-3549. https://doi.org/10.2174/1573399819666221102113217
    24. Phil Addis, Utsav Bali, Frank Baron, Adrian Campbell, Steven Harborne, Liz Jagger, Gavin Milne, Martin Pearce, Elizabeth M Rosethorne, Rupert Satchell, Denise Swift, Barbara Young, John F Unitt. Key aspects of modern GPCR drug discovery. SLAS Discovery 2023, 93 https://doi.org/10.1016/j.slasd.2023.08.007
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    26. Haoxi Li, Nikhil M. Urs, Nicole Horenstein. Computational insights into ligand–induced G protein and β-arrestin signaling of the dopamine D1 receptor. Journal of Computer-Aided Molecular Design 2023, 37 (5-6) , 227-244. https://doi.org/10.1007/s10822-023-00503-7
    27. Fabian Liessmann, Georg Künze, Jens Meiler. Improving the Modeling of Extracellular Ligand Binding Pockets in RosettaGPCR for Conformational Selection. International Journal of Molecular Sciences 2023, 24 (9) , 7788. https://doi.org/10.3390/ijms24097788
    28. Zoe Li, Jie Liu, Fan Dong, Nancy Chang, Ruili Huang, Menghang Xia, Tucker A. Patterson, Huixiao Hong. Three-Dimensional Structural Insights Have Revealed the Distinct Binding Interactions of Agonists, Partial Agonists, and Antagonists with the µ Opioid Receptor. International Journal of Molecular Sciences 2023, 24 (8) , 7042. https://doi.org/10.3390/ijms24087042
    29. Vern Lewis, Emma M. Bonniwell, Janelle K. Lanham, Abdi Ghaffari, Hooshmand Sheshbaradaran, Andrew B. Cao, Maggie M. Calkins, Mario Alberto Bautista-Carro, Emily Arsenault, Andre Telfer, Fatimeh-Frouh Taghavi-Abkuh, Nicholas J. Malcolm, Fatema El Sayegh, Alfonso Abizaid, Yasmin Schmid, Kathleen Morton, Adam L. Halberstadt, Argel Aguilar-Valles, John D. McCorvy. A non-hallucinogenic LSD analog with therapeutic potential for mood disorders. Cell Reports 2023, 42 (3) , 112203. https://doi.org/10.1016/j.celrep.2023.112203
    30. Rebecca Ferrisi, Beatrice Polini, Caterina Ricardi, Francesca Gado, Kawthar A. Mohamed, Giovanna Baron, Salvatore Faiella, Giulio Poli, Simona Rapposelli, Giuseppe Saccomanni, Giancarlo Aldini, Grazia Chiellini, Robert B. Laprairie, Clementina Manera, Gabriella Ortore. New Insights into Bitopic Orthosteric/Allosteric Ligands of Cannabinoid Receptor Type 2. International Journal of Molecular Sciences 2023, 24 (3) , 2135. https://doi.org/10.3390/ijms24032135
    31. Shuai Luo, Peng Zhang, Wei Miao, Jie Xiong. Genome-Wide Identification of G Protein-Coupled Receptors in Ciliated Eukaryotes. International Journal of Molecular Sciences 2023, 24 (4) , 3869. https://doi.org/10.3390/ijms24043869
    32. Tatiana Hillman. A Predictive Model for Identifying the Most Effective Anti-CCR5 Monoclonal Antibody. Archives of Pharmacy Practice 2023, 14 (1) , 40-49. https://doi.org/10.51847/d9m2zUfqr4
    33. Raudah Lazim, Yoonji Lee, Pratanphorn Nakliang, Sun Choi. Importance of Structure and Dynamics in the Rational Drug Design of G Protein‐Coupled Receptor ( GPCR ) Modulators. 2022, 424-457. https://doi.org/10.1002/9781119564782.ch13
    34. Gunnar Nordvall, Pontus Forsell, Johan Sandin. Neurotrophin-targeted therapeutics: A gateway to cognition and more?. Drug Discovery Today 2022, 27 (10) , 103318. https://doi.org/10.1016/j.drudis.2022.07.003
    35. Xiaoqin Zhang, Wenqian Zhou, Yangyang Niu, Saiya Zhu, Yingying Zhang, Xiaogang Li, Chen Yu. Lysyl oxidase promotes renal fibrosis via accelerating collagen cross‐link driving by β‐arrestin/ ERK / STAT3 pathway. The FASEB Journal 2022, 36 (8) https://doi.org/10.1096/fj.202200573R
    36. Luciana M. Leo, Rufaida Al-Zoubi, Dow P. Hurst, Anna P. Stephan, Pingwei Zhao, Douglas G. Tilley, Elke Miess, Stefan Schulz, Mary E. Abood, Patricia H. Reggio. The NPXXY Motif Regulates β-Arrestin Recruitment by the CB1 Cannabinoid Receptor. Cannabis and Cannabinoid Research 2022, 352 https://doi.org/10.1089/can.2021.0223
    37. Qi Mao, Bingjie Zhang, Sheng Tian, Wangzhi Qin, Jiaojiao Chen, Xi-Ping Huang, Ye Xin, Huicui Yang, Xue-Chu Zhen, Wenqing Shui, Na Ye. Structural optimizations and bioevaluation of N-H aporphine analogues as Gq-biased and selective serotonin 5-HT2C receptor agonists. Bioorganic Chemistry 2022, 123 , 105795. https://doi.org/10.1016/j.bioorg.2022.105795
    38. Jaromir Myslivecek. Dopamine and Dopamine-Related Ligands Can Bind Not Only to Dopamine Receptors. Life 2022, 12 (5) , 606. https://doi.org/10.3390/life12050606
    39. Jun Xu, Sheng Cao, Harald Hübner, Dorothée Weikert, Geng Chen, Qiuyuan Lu, Daopeng Yuan, Peter Gmeiner, Zheng Liu, Yang Du. Structural insights into ligand recognition, activation, and signaling of the α 2A adrenergic receptor. Science Advances 2022, 8 (9) https://doi.org/10.1126/sciadv.abj5347
    40. Fuhui Zhang, Yuan Yuan, Yichi Chen, Jianfang Chen, Yanzhi Guo, Xuemei Pu. Molecular insights into the allosteric coupling mechanism between an agonist and two different transducers for μ-opioid receptors. Physical Chemistry Chemical Physics 2022, 24 (9) , 5282-5293. https://doi.org/10.1039/D1CP05736G
    41. Andrew A Somogyi, Stefan T Musolino, Daniel T Barratt. New pharmacological perspectives and therapeutic options for opioids: Differences matter. Anaesthesia and Intensive Care 2022, 50 (1-2) , 127-140. https://doi.org/10.1177/0310057X211063891
    42. Paipai Guo, Yu Tai, Manman Wang, Hanfei Sun, Lingling Zhang, Wei Wei, Yang K. Xiang, Qingtong Wang. Gα12 and Gα13: Versatility in Physiology and Pathology. Frontiers in Cell and Developmental Biology 2022, 10 https://doi.org/10.3389/fcell.2022.809425
    43. Michael Ippolito, Francesco De Pascali, Asuka Inoue, Jeffrey L. Benovic. Phenylalanine 193 in Extracellular Loop 2 of the β 2 -Adrenergic Receptor Coordinates β -Arrestin Interaction. Molecular Pharmacology 2022, 101 (2) , 87-94. https://doi.org/10.1124/molpharm.121.000332
    44. Dehua Yang, Qingtong Zhou, Viktorija Labroska, Shanshan Qin, Sanaz Darbalaei, Yiran Wu, Elita Yuliantie, Linshan Xie, Houchao Tao, Jianjun Cheng, Qing Liu, Suwen Zhao, Wenqing Shui, Yi Jiang, Ming-Wei Wang. G protein-coupled receptors: structure- and function-based drug discovery. Signal Transduction and Targeted Therapy 2021, 6 (1) https://doi.org/10.1038/s41392-020-00435-w
    45. Jolien De Neve, Thomas M. A. Barlow, Dirk Tourwé, Frédéric Bihel, Frédéric Simonin, Steven Ballet. Comprehensive overview of biased pharmacology at the opioid receptors: biased ligands and bias factors. RSC Medicinal Chemistry 2021, 12 (6) , 828-870. https://doi.org/10.1039/D1MD00041A
    46. Shintaro Maeda, Yuki Shiimura, Hidetsugu Asada, Kunio Hirata, Fangjia Luo, Eriko Nango, Nobuo Tanaka, Masayasu Toyomoto, Asuka Inoue, Junken Aoki, So Iwata, Masatoshi Hagiwara. Endogenous agonist–bound S1PR3 structure reveals determinants of G protein–subtype bias. Science Advances 2021, 7 (24) https://doi.org/10.1126/sciadv.abf5325
    47. Rosmara Infantino, Consalvo Mattia, Pamela Locarini, Antonio Luigi Pastore, Sabatino Maione, Livio Luongo. Buprenorphine: Far Beyond the “Ceiling”. Biomolecules 2021, 11 (6) , 816. https://doi.org/10.3390/biom11060816
    48. Joaquim Azevedo Neto, Chiara Ruzza, Chiara Sturaro, Davide Malfacini, Salvatore Pacifico, Nurulain T. Zaveri, Girolamo Calò. Functional Selectivity Does Not Predict Antinociceptive/Locomotor Impairing Potencies of NOP Receptor Agonists. Frontiers in Neuroscience 2021, 15 https://doi.org/10.3389/fnins.2021.657153
    49. Ying Wang, Zhengtian Yu, Wen Xiao, Shaoyong Lu, Jian Zhang. Allosteric binding sites at the receptor–lipid bilayer interface: novel targets for GPCR drug discovery. Drug Discovery Today 2021, 26 (3) , 690-703. https://doi.org/10.1016/j.drudis.2020.12.001
    50. Xuan Jiang, Shuxiang Li, Hongbin Zhang, Liang-Liang Wang. Discovery of potentially biased agonists of mu-opioid receptor (MOR) through molecular docking, pharmacophore modeling, and MD simulation. Computational Biology and Chemistry 2021, 90 , 107405. https://doi.org/10.1016/j.compbiolchem.2020.107405
    51. Gianfabio Giorgioni, Fabio Del Bello, Pegi Pavletić, Wilma Quaglia, Luca Botticelli, Carlo Cifani, Emanuela Micioni Di Bonaventura, Maria Vittoria Micioni Di Bonaventura, Alessandro Piergentili. Recent findings leading to the discovery of selective dopamine D4 receptor ligands for the treatment of widespread diseases. European Journal of Medicinal Chemistry 2021, 212 , 113141. https://doi.org/10.1016/j.ejmech.2020.113141
    52. Mario Zanaty, Fernando A.C. Seara, Pablo Nakagawa, Guorui Deng, Natalia M. Mathieu, Kirthikaa Balapattabi, Sadashiva S. Karnik, Justin L. Grobe, Curt D. Sigmund. β-Arrestin–Biased Agonist Targeting the Brain AT 1 R (Angiotensin II Type 1 Receptor) Increases Aversion to Saline and Lowers Blood Pressure in Deoxycorticosterone Acetate–Salt Hypertension. Hypertension 2021, 77 (2) , 420-431. https://doi.org/10.1161/HYPERTENSIONAHA.120.15793
    53. Brittany M. Craft, Danial E. Baker. Oliceridine. Hospital Pharmacy 2021, , 001857872098713. https://doi.org/10.1177/0018578720987137
    54. Benjamin E. Blass. Classical targets in drug discovery. 2021, 111-183. https://doi.org/10.1016/B978-0-12-817214-8.00003-8
    55. Eline Pottie, Peter Dedecker, Christophe P. Stove. Identification of psychedelic new psychoactive substances (NPS) showing biased agonism at the 5-HT2AR through simultaneous use of β-arrestin 2 and miniGαq bioassays. Biochemical Pharmacology 2020, 182 , 114251. https://doi.org/10.1016/j.bcp.2020.114251
    56. Álvaro Velasco‐Rubio, Jesús A. Varela, Carlos Saá. Recent Advances in Transition‐Metal‐Catalyzed Oxidative Annulations to Benzazepines and Benzodiazepines. Advanced Synthesis & Catalysis 2020, 362 (22) , 4861-4875. https://doi.org/10.1002/adsc.202000808
    57. Attila Egyed, Katalin Domány-Kovács, Bence Koványi, Ferenc Horti, Dalma Kurkó, Dóra Judit Kiss, Gáspár Pándy-Szekeres, István Greiner, György M. Keserű. Controlling receptor function from the extracellular vestibule of G-protein coupled receptors. Chemical Communications 2020, 56 (91) , 14167-14170. https://doi.org/10.1039/D0CC05532H
    58. Louiza Belkacemi, Nissar A. Darmani. Dopamine receptors in emesis: Molecular mechanisms and potential therapeutic function. Pharmacological Research 2020, 161 , 105124. https://doi.org/10.1016/j.phrs.2020.105124
    59. Joaquim Azevedo Neto, Anna Costanzini, Roberto De Giorgio, David G. Lambert, Chiara Ruzza, Girolamo Calò. Biased versus Partial Agonism in the Search for Safer Opioid Analgesics. Molecules 2020, 25 (17) , 3870. https://doi.org/10.3390/molecules25173870
    60. Mark W. Majewski, Disha M. Gandhi, Trudy Holyst, Zhengli Wang, Irene Hernandez, Ricardo Rosas, Jieqing Zhu, Hartmut Weiler, Chris Dockendorff. Synthesis and initial pharmacology of dual-targeting ligands for putative complexes of integrin αVβ3 and PAR2. RSC Medicinal Chemistry 2020, 11 (8) , 940-949. https://doi.org/10.1039/D0MD00098A
    61. Amirhossein Mafi, Soo-Kyung Kim, William A. Goddard. Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor. Proceedings of the National Academy of Sciences 2020, 117 (28) , 16346-16355. https://doi.org/10.1073/pnas.1918264117
    62. Maria M. Shchepinova, Aylin C. Hanyaloglu, Gary S. Frost, Edward W. Tate. Chemical biology of noncanonical G protein–coupled receptor signaling: Toward advanced therapeutics. Current Opinion in Chemical Biology 2020, 56 , 98-110. https://doi.org/10.1016/j.cbpa.2020.04.012
    63. Carl-Mikael Suomivuori, Naomi R. Latorraca, Laura M. Wingler, Stephan Eismann, Matthew C. King, Alissa L. W. Kleinhenz, Meredith A. Skiba, Dean P. Staus, Andrew C. Kruse, Robert J. Lefkowitz, Ron O. Dror. Molecular mechanism of biased signaling in a prototypical G protein–coupled receptor. Science 2020, 367 (6480) , 881-887. https://doi.org/10.1126/science.aaz0326
    64. Alexander Heifetz, Andrea Townsend-Nicholson. Characterizing Rhodopsin-Arrestin Interactions with the Fragment Molecular Orbital (FMO) Method. 2020, 177-186. https://doi.org/10.1007/978-1-0716-0282-9_12
    65. Hirotaka Mizuno, Yasuyuki Kihara. Druggable Lipid GPCRs: Past, Present, and Prospects. 2020, 223-258. https://doi.org/10.1007/978-3-030-50621-6_10
    66. Qingtong Zhou, Dehua Yang, Meng Wu, Yu Guo, Wanjing Guo, Li Zhong, Xiaoqing Cai, Antao Dai, Wonjo Jang, Eugene I Shakhnovich, Zhi-Jie Liu, Raymond C Stevens, Nevin A Lambert, M Madan Babu, Ming-Wei Wang, Suwen Zhao. Common activation mechanism of class A GPCRs. eLife 2019, 8 https://doi.org/10.7554/eLife.50279
    67. Rita Turnaturi, Santina Chiechio, Loredana Salerno, Antonio Rescifina, Valeria Pittalà, Giuseppina Cantarella, Emilia Tomarchio, Carmela Parenti, Lorella Pasquinucci. Progress in the development of more effective and safer analgesics for pain management. European Journal of Medicinal Chemistry 2019, 183 , 111701. https://doi.org/10.1016/j.ejmech.2019.111701
    68. Elise Wouters, Jolien Walraed, Samuel D. Banister, Christophe P. Stove. Insights into biased signaling at cannabinoid receptors: synthetic cannabinoid receptor agonists. Biochemical Pharmacology 2019, 169 , 113623. https://doi.org/10.1016/j.bcp.2019.08.025
    69. Taneisha Gillyard, Katelyn Fowler, Savannah Y. Williams, Roger D. Cone. Obesity‐associated mutant melanocortin‐4 receptors with normal Gα s coupling frequently exhibit other discoverable pharmacological and biochemical defects. Journal of Neuroendocrinology 2019, 31 (10) https://doi.org/10.1111/jne.12795
    70. Michael L. Martini, Sean N. Neifert, J Mocco, Fedor Panov, Winona Tse, Ruth H. Walker, Jian Jin, Fiona Gupta. Recent Advances in the Development of Experimental Therapeutics for Levodopa-Induced Dyskinesia. Journal of Movement Disorders 2019, 12 (3) , 161-165. https://doi.org/10.14802/jmd.19029
    71. Daniel E. Felsing, Manish K. Jain, John A. Allen. Advances in Dopamine D1 Receptor Ligands for Neurotherapeutics. Current Topics in Medicinal Chemistry 2019, 19 (16) , 1365-1380. https://doi.org/10.2174/1568026619666190712210903
    72. Katarzyna Rzęsikowska, Anna Krawczuk, Justyna Kalinowska-Tłuścik. Electrostatic potential and non-covalent interactions analysis for the design of selective 5-HT7 ligands. Journal of Molecular Graphics and Modelling 2019, 91 , 130-139. https://doi.org/10.1016/j.jmgm.2019.06.007
    73. Ammar A.H. Azzam, John McDonald, David G. Lambert. Hot topics in opioid pharmacology: mixed and biased opioids. British Journal of Anaesthesia 2019, 122 (6) , e136-e145. https://doi.org/10.1016/j.bja.2019.03.006
    74. Marcel Bermudez, Trung Ngoc Nguyen, Christian Omieczynski, Gerhard Wolber. Strategies for the discovery of biased GPCR ligands. Drug Discovery Today 2019, 24 (4) , 1031-1037. https://doi.org/10.1016/j.drudis.2019.02.010
    75. Terry Kenakin, . Biased Receptor Signaling in Drug Discovery. Pharmacological Reviews 2019, 71 (2) , 267-315. https://doi.org/10.1124/pr.118.016790
    76. Javier García‐Cárceles. Novel Strategies Targeting G ‐Protein‐Coupled Receptors: An Overview. 2018, 1-9. https://doi.org/10.1002/9780470015902.a0028406
    77. Paula Morales, Pilar Goya, Nadine Jagerovic. Emerging strategies targeting CB2 cannabinoid receptor: Biased agonism and allosterism. Biochemical Pharmacology 2018, 157 , 8-17. https://doi.org/10.1016/j.bcp.2018.07.031

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