Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Targeting receptor complexes: a new dimension in drug discovery

Nature Reviews Drug Discovery volume 19, pages 884–901 (2020)Cite this article

Subjects

Abstract

Targeting receptor proteins, such as ligand-gated ion channels and G protein-coupled receptors, has directly enabled the discovery of most drugs developed to modulate receptor signalling. However, as the search for novel and improved drugs continues, an innovative approach — targeting receptor complexes — is emerging. Receptor complexes are composed of core receptor proteins and receptor-associated proteins, which have profound effects on the overall receptor structure, function and localization. Hence, targeting key protein–protein interactions within receptor complexes provides an opportunity to develop more selective drugs with fewer side effects. In this Review, we discuss our current understanding of ligand-gated ion channel and G protein-coupled receptor complexes and discuss strategies for their pharmacological modulation. Although such strategies are still in preclinical development for most receptor complexes, they exemplify how receptor complexes can be drugged, and lay the groundwork for this nascent area of research.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Structure and function of receptor complexes.
Fig. 2: Strategies for targeting receptor complexes.
Fig. 3: Targeting ligand-gated ion channel complexes.
Fig. 4: Targeting GPCR complexes.

Similar content being viewed by others

References

  1. Santos, R. et al. A comprehensive map of molecular drug targets. Nat. Rev. Drug Discov. 16, 19–34 (2017).

    Article  CAS  PubMed  Google Scholar 

  2. Maher, M. P., Matta, J. A., Gu, S., Seierstad, M. & Bredt, D. S. Getting a handle on neuropharmacology by targeting receptor-associated proteins. Neuron 96, 989–1001 (2017).

    Article  CAS  PubMed  Google Scholar 

  3. Huttlin, E. L. et al. Architecture of the human interactome defines protein communities and disease networks. Nature 545, 505–509 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Rual, J. F. et al. Towards a proteome-scale map of the human protein-protein interaction network. Nature 437, 1173–1178 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Uhlen, M. et al. Proteomics. Tissue-based map of the human proteome. Science 347, 1260419 (2015).

    Article  PubMed  CAS  Google Scholar 

  6. Hein, M. Y. et al. A human interactome in three quantitative dimensions organized by stoichiometries and abundances. Cell 163, 712–723 (2015).

    Article  CAS  PubMed  Google Scholar 

  7. Huttlin, E. L. et al. The BioPlex network: a systematic exploration of the human interactome. Cell 162, 425–440 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Pin, J. P. & Bettler, B. Organization and functions of mGlu and GABAB receptor complexes. Nature 540, 60–68 (2016).

    Article  CAS  PubMed  Google Scholar 

  9. Osten, P. & Stern-Bach, Y. Learning from stargazin: the mouse, the phenotype and the unexpected. Curr. Opin. Neurobiol. 16, 275–280 (2006).

    Article  CAS  PubMed  Google Scholar 

  10. Isom, L. L., De Jongh, K. S. & Catterall, W. A. Auxiliary subunits of voltage-gated ion channels. Neuron 12, 1183–1194 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Jackson, A. C. & Nicoll, R. A. The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits. Neuron 70, 178–199 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yan, D. & Tomita, S. Defined criteria for auxiliary subunits of glutamate receptors. J. Physiol. 590, 21–31 (2012).

    Article  CAS  PubMed  Google Scholar 

  13. Pfeiffer, F., Graham, D. & Betz, H. Purification by affinity chromatography of the glycine receptor of rat spinal cord. J. Biol. Chem. 257, 9389–9393 (1982).

    Article  CAS  PubMed  Google Scholar 

  14. Tretter, V. et al. The clustering of GABAA receptor subtypes at inhibitory synapses is facilitated via the direct binding of receptor alpha 2 subunits to gephyrin. J. Neurosci. 28, 1356–1365 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Maric, H. M. et al. Gephyrin-binding peptides visualize postsynaptic sites and modulate neurotransmission. Nat. Chem. Biol. 13, 153–160 (2017).

    Article  CAS  PubMed  Google Scholar 

  16. Maric, H. M. et al. Molecular basis of the alternative recruitment of GABAA versus glycine receptors through gephyrin. Nat. Commun. 5, 5767 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Li, J. et al. Artemisinins target GABAA receptor signaling and impair alpha cell identity. Cell 168, 86–100 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Han, W. et al. Shisa7 is a GABAA receptor auxiliary subunit controlling benzodiazepine actions. Science 366, 246–250 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Letts, V. A. et al. The mouse stargazer gene encodes a neuronal Ca2+-channel gamma subunit. Nat. Genet. 19, 340–347 (1998).

    Article  CAS  PubMed  Google Scholar 

  20. Chen, L. et al. Stargazin regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Hashimoto, K. et al. Impairment of AMPA receptor function in cerebellar granule cells of ataxic mutant mouse stargazer. J. Neurosci. 19, 6027–6036 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tomita, S. et al. Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435, 1052–1058 (2005).

    Article  CAS  PubMed  Google Scholar 

  23. Tomita, S. et al. Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. J. Cell Biol. 161, 805–816 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Twomey, E. C., Yelshanskaya, M. V., Grassucci, R. A., Frank, J. & Sobolevsky, A. I. Elucidation of AMPA receptor-stargazin complexes by cryo-electron microscopy. Science 353, 83–86 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Zhao, Y., Chen, S., Yoshioka, C., Baconguis, I. & Gouaux, E. Architecture of fully occupied GluA2 AMPA receptor-TARP complex elucidated by cryo-EM. Nature 536, 108–111 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Herguedas, B. et al. Architecture of the heteromeric GluA1/2 AMPA receptor in complex with the auxiliary subunit TARP gamma8. Science 364, eaav9011 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Twomey, E. C., Yelshanskaya, M. V., Grassucci, R. A., Frank, J. & Sobolevsky, A. I. Structural bases of desensitization in AMPA receptor-auxiliary subunit complexes. Neuron 94, 569–580.e565 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Twomey, E. C., Yelshanskaya, M. V., Grassucci, R. A., Frank, J. & Sobolevsky, A. I. Channel opening and gating mechanism in AMPA-subtype glutamate receptors. Nature 549, 60–65 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Schwenk, J. et al. Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323, 1313–1319 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Schwenk, J. et al. Regional diversity and developmental dynamics of the AMPA-receptor proteome in the mammalian brain. Neuron 84, 41–54 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Schwenk, J. et al. High-resolution proteomics unravel architecture and molecular diversity of native AMPA receptor complexes. Neuron 74, 621–633 (2012). Using high-resolution proteomics, this study showcases the complexity of AMPAR complexes by identifying 21 receptor-associated proteins.

    Article  CAS  PubMed  Google Scholar 

  32. Frank, R. A. et al. NMDA receptors are selectively partitioned into complexes and supercomplexes during synapse maturation. Nat. Commun. 7, 11264 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lei, N., Mellem, J. E., Brockie, P. J., Madsen, D. M. & Maricq, A. V. NRAP-1 is a presynaptically released NMDA receptor auxiliary protein that modifies synaptic strength. Neuron 96, 1303–1316 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Jackson, D. S., Ramachandrappa, S., Clark, A. J. & Chan, L. F. Melanocortin receptor accessory proteins in adrenal disease and obesity. Front. Neurosci. 9, 213 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Xu, A. et al. Identification of novel putative membrane proteins selectively expressed during adipose conversion of 3T3-L1 cells. Biochemical Biophysical Res. Commun. 293, 1161–1167 (2002).

    Article  CAS  Google Scholar 

  36. Metherell, L. A. et al. Mutations in MRAP, encoding a new interacting partner of the ACTH receptor, cause familial glucocorticoid deficiency type 2. Nat. Genet. 37, 166–170 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Chan, L. F. et al. MRAP and MRAP2 are bidirectional regulators of the melanocortin receptor family. Proc. Natl Acad. Sci. USA 106, 6146–6151 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Asai, M. et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science 341, 275–278 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sebag, J. A., Zhang, C., Hinkle, P. M., Bradshaw, A. M. & Cone, R. D. Developmental control of the melanocortin-4 receptor by MRAP2 proteins in zebrafish. Science 341, 278–281 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Schwenk, J. et al. Native GABA(B) receptors are heteromultimers with a family of auxiliary subunits. Nature 465, 231–235 (2010). This study demonstrates that KCTD proteins are auxiliary GABAB receptor subunits that confer the kinetic properties of native receptors to the recombinant receptors.

    Article  CAS  PubMed  Google Scholar 

  41. Schwenk, J. et al. Modular composition and dynamics of native GABAB receptors identified by high-resolution proteomics. Nat. Neurosci. 19, 233–242 (2016).

    Article  CAS  PubMed  Google Scholar 

  42. Belliotti, T. R. et al. Structure-activity relationships of pregabalin and analogues that target the alpha(2)-delta protein. J. Med. Chem. 48, 2294–2307 (2005).

    Article  CAS  PubMed  Google Scholar 

  43. Gee, N. S. et al. The novel anticonvulsant drug, gabapentin (Neurontin), binds to the alpha2delta subunit of a calcium channel. J. Biol. Chem. 271, 5768–5776 (1996).

    Article  CAS  PubMed  Google Scholar 

  44. Lee, K. P. K., Chen, J. & MacKinnon, R. Molecular structure of human KATP in complex with ATP and ADP. eLife 6, e32481 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Wu, J. X. et al. Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels. Protein Cell 9, 553–567 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Henquin, J. C. The fiftieth anniversary of hypoglycaemic sulphonamides. How did the mother compound work? Diabetologia 35, 907–912 (1992).

    Article  CAS  PubMed  Google Scholar 

  47. Aguilar-Bryan, L. et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268, 423–426 (1995).

    Article  CAS  PubMed  Google Scholar 

  48. Inagaki, N. et al. Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270, 1166–1170 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Martin, G. M., Kandasamy, B., DiMaio, F., Yoshioka, C. & Shyng, S. L. Anti-diabetic drug binding site in a mammalian KATP channel revealed by cryo-EM. eLife 6, e31054 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Mehta, R. I. et al. Sur1-Trpm4 cation channel expression in human cerebral infarcts. J. Neuropathol. Exp. Neurol. 74, 835–849 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Sala-Rabanal, M., Wang, S. & Nichols, C. G. On potential interactions between non-selective cation channel TRPM4 and sulfonylurea receptor SUR1. J. Biol. Chem. 287, 8746–8756 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Simard, J. M. et al. Newly expressed SUR1-regulated NCCa-ATP channel mediates cerebral edema after ischemic stroke. Nat. Med. 12, 433–440 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. King, Z. A., Sheth, K. N., Kimberly, W. T. & Simard, J. M. Profile of intravenous glyburide for the prevention of cerebral edema following large hemispheric infarction: evidence to date. Drug Des. Devel. Ther. 12, 2539–2552 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Sheth, K. N. et al. Human data supporting glyburide in ischemic stroke. Acta Neurochir. Suppl. 121, 13–18 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  55. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02864953 (2020).

  56. Granier, S. et al. Structure of the delta-opioid receptor bound to naltrindole. Nature 485, 400–404 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Manglik, A. et al. Crystal structure of the micro-opioid receptor bound to a morphinan antagonist. Nature 485, 321–326 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Wu, H. et al. Structure of the human kappa-opioid receptor in complex with JDTic. Nature 485, 327–332 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Foster, D. J. & Conn, P. J. Allosteric modulation of GPCRs: new insights and potential utility for treatment of schizophrenia and other CNS disorders. Neuron 94, 431–446 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Scott, D. E., Bayly, A. R., Abell, C. & Skidmore, J. Small molecules, big targets: drug discovery faces the protein-protein interaction challenge. Nat. Rev. Drug Discov. 15, 533–550 (2016).

    Article  CAS  PubMed  Google Scholar 

  61. Ran, X. & Gestwicki, J. E. Inhibitors of protein-protein interactions (PPIs): an analysis of scaffold choices and buried surface area. Curr. Opin. Chem. Biol. 44, 75–86 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Neves, V., Aires-da-Silva, F., Corte-Real, S. & Castanho, M. A. R. B. Antibody approaches to treat brain diseases. Trends Biotechnol. 34, 36–48 (2016).

    Article  CAS  Google Scholar 

  63. Hutchings, C. J., Koglin, M., Olson, W. C. & Marshall, F. H. Opportunities for therapeutic antibodies directed at G-protein-coupled receptors. Nat. Rev. Drug Discov. 16, 787–810 (2017).

    Article  CAS  PubMed  Google Scholar 

  64. Wulff, H., Christophersen, P., Colussi, P., Chandy, K. G. & Yarov-Yarovoy, V. Antibodies and venom peptides: new modalities for ion channels. Nat. Rev. Drug Discov. 18, 339–357 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Hutchings, C. J., Colussi, P. & Clark, T. G. Ion channels as therapeutic antibody targets. MAbs 11, 265–296 (2019).

    Article  CAS  PubMed  Google Scholar 

  66. Edvinsson, L., Haanes, K. A., Warfvinge, K. & Krause, D. N. CGRP as the target of new migraine therapies - successful translation from bench to clinic. Nat. Rev. Neurol. 14, 338–350 (2018).

    Article  CAS  PubMed  Google Scholar 

  67. Köhler, G. & Milstein, C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256, 495–497 (1975).

    Article  PubMed  Google Scholar 

  68. Frenzel, A., Schirrmann, T. & Hust, M. Phage display-derived human antibodies in clinical development and therapy. MAbs 8, 1177–1194 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Smith, G. P. Filamentous fusion phage: novel expression vectors that display cloned antigens on the virion surface. Science 228, 1315–1317 (1985).

    Article  CAS  PubMed  Google Scholar 

  70. Bagal, S. K. et al. Ion channels as therapeutic targets: a drug discovery perspective. J. Med. Chem. 56, 593–624 (2013).

    Article  CAS  PubMed  Google Scholar 

  71. Zhang, R. & Xie, X. Tools for GPCR drug discovery. Acta Pharmacol. Sin. 33, 372–384 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Macarron, R. et al. Impact of high-throughput screening in biomedical research. Nat. Rev. Drug Discov. 10, 188–195 (2011).

    Article  CAS  PubMed  Google Scholar 

  73. Gardinier, K. M. et al. Discovery of the first α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonist dependent upon transmembrane AMPA receptor regulatory protein (TARP) γ-8. J. Med. Chem. 59, 4753–4768 (2016). Together with Kato et al. (2016), this reports the first AMPAR–TARPγ8-selective small-molecule antagonist, which mitigates side effects associated with global AMPAR inhibition.

    Article  CAS  PubMed  Google Scholar 

  74. Kato, A. S. et al. Forebrain-selective AMPA-receptor antagonism guided by TARP gamma-8 as an antiepileptic mechanism. Nat. Med. 22, 1496–1501 (2016). Together with Gardiniere et al. (2016), this reports the first AMPAR–TARPγ8-selective small-molecule antagonist.

    Article  CAS  PubMed  Google Scholar 

  75. Maher, M. P. et al. Discovery and characterization of AMPA receptor modulators selective for TARP-gamma8. J. Pharmacol. Exp. Ther. 357, 394–414 (2016).

    Article  CAS  PubMed  Google Scholar 

  76. Ottl, J., Leder, L., Schaefer, J. V. & Dumelin, C. E. Encoded library technologies as integrated lead finding platforms for drug discovery. Molecules 24, 1629 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  77. Ahn, S. et al. Allosteric “beta-blocker” isolated from a DNA-encoded small molecule library. Proc. Natl Acad. Sci. USA 114, 1708–1713 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Schapira, M., Calabrese, M. F., Bullock, A. N. & Crews, C. M. Targeted protein degradation: expanding the toolbox. Nat. Rev. Drug Discov. 18, 949–963 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. Aarts, M. et al. Treatment of ischemic brain damage by perturbing NMDA receptor- PSD-95 protein interactions. Science 298, 846–850 (2002). This article describes the development of the first PSD95 inhibitor NA-1 and how it protects against ischaemic damage in rats.

    Article  CAS  PubMed  Google Scholar 

  80. Bach, A. et al. A high-affinity, dimeric inhibitor of PSD-95 bivalently interacts with PDZ1-2 and protects against ischemic brain damage. Proc. Natl Acad. Sci. USA 109, 3317–3322 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Fosgerau, K. & Hoffmann, T. Peptide therapeutics: current status and future directions. Drug Discov. Today 20, 122–128 (2015).

    Article  CAS  PubMed  Google Scholar 

  82. Henninot, A., Collins, J. C. & Nuss, J. M. The current state of peptide drug discovery: back to the future? J. Med. Chem. 61, 1382–1414 (2018).

    Article  CAS  PubMed  Google Scholar 

  83. Lau, Y. H., de Andrade, P., Wu, Y. & Spring, D. R. Peptide stapling techniques based on different macrocyclisation chemistries. Chem. Soc. Rev. 44, 91–102 (2015).

    Article  CAS  PubMed  Google Scholar 

  84. Frank, R. Spot-synthesis: an easy technique for the positionally addressable, parallel chemical synthesis on a membrane support. Tetrahedron 48, 9217–9232 (1992).

    Article  CAS  Google Scholar 

  85. Galan, A. et al. Library-based display technologies: where do we stand? Mol. Biosyst. 12, 2342–2358 (2016).

    Article  CAS  PubMed  Google Scholar 

  86. Huang, Y., Wiedmann, M. M. & Suga, H. RNA display methods for the discovery of bioactive macrocycles. Chem. Rev. 119, 10360–10391 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Rogers, J. M., Passioura, T. & Suga, H. Nonproteinogenic deep mutational scanning of linear and cyclic peptides. Proc. Natl. Acad. Sci. USA 115, 10959–10964 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Passioura, T. & Suga, H. A RaPID way to discover nonstandard macrocyclic peptide modulators of drug targets. Chem. Commun. 53, 1931–1940 (2017).

    Article  CAS  Google Scholar 

  89. Weidmann, J. & Craik, D. J. Discovery, structure, function, and applications of cyclotides: circular proteins from plants. J. Exp. Bot. 67, 4801–4812 (2016).

    Article  CAS  PubMed  Google Scholar 

  90. Green, M. & Loewenstein, P. M. Autonomous functional domains of chemically synthesized human immunodeficiency virus tat trans-activator protein. Cell 55, 1179–1188 (1988).

    Article  CAS  PubMed  Google Scholar 

  91. Frankel, A. D. & Pabo, C. O. Cellular uptake of the tat protein from human immunodeficiency virus. Cell 55, 1189–1193 (1988).

    Article  CAS  PubMed  Google Scholar 

  92. El-Andaloussi, S., Jarver, P., Johansson, H. J. & Langel, U. Cargo-dependent cytotoxicity and delivery efficacy of cell-penetrating peptides: a comparative study. Biochem. J. 407, 285–292 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Qian, Z. et al. Discovery and mechanism of highly efficient cyclic cell-penetrating peptides. Biochemistry 55, 2601–2612 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Peraro, L. & Kritzer, J. A. Emerging methods and design principles for cell-penetrant peptides. Angew. Chem. Int. Ed. 57, 11868–11881 (2018).

    Article  CAS  Google Scholar 

  95. Keating, G. M. Netupitant/palonosetron: a review in the prevention of chemotherapy-induced nausea and vomiting. Drugs 75, 2131–2141 (2015).

    Article  CAS  PubMed  Google Scholar 

  96. Smart, T. G. & Stephenson, F. A. A half century of gamma-aminobutyric acid. Brain Neurosci. Adv. 3, 2398212819858249 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  97. Jordan, C. J. & Xi, Z. X. Discovery and development of varenicline for smoking cessation. Expert Opin. Drug Discov. 13, 671–683 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Kraus, C. et al. The influence of ketamine on drug discovery in depression. Drug Discov. Today 24, 2033–243 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yang, Y. et al. Ketamine blocks bursting in the lateral habenula to rapidly relieve depression. Nature 554, 317–322 (2018).

    Article  CAS  PubMed  Google Scholar 

  100. Liriano, F., Hatten, C. & Schwartz, T. L. Ketamine as treatment for post-traumatic stress disorder: a review. Drugs Context 8, 212305 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  101. Preskorn, S. H. et al. An innovative design to establish proof of concept of the antidepressant effects of the NR2B subunit selective N-methyl-D-aspartate antagonist, CP-101,606, in patients with treatment-refractory major depressive disorder. J. Clin. Psychopharmacol. 28, 631–637 (2008).

    Article  CAS  PubMed  Google Scholar 

  102. Ogden, K. K. & Traynelis, S. F. New advances in NMDA receptor pharmacology. Trends Pharmacol. Sci. 32, 726–733 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Olney, J. W., Labruyere, J. & Price, M. T. Pathological changes induced in cerebrocortical neurons by phencyclidine and related drugs. Science 244, 1360–1362 (1989).

    Article  CAS  PubMed  Google Scholar 

  104. Addy, C. et al. Single-dose administration of MK-0657, an NR2B-selective NMDA antagonist, does not result in clinically meaningful improvement in motor function in patients with moderate Parkinson’s disease. J. Clin. Pharmacol. 49, 856–864 (2009).

    Article  CAS  PubMed  Google Scholar 

  105. Kornau, H. C., Schenker, L. T., Kennedy, M. B. & Seeburg, P. H. Domain interaction between NMDA receptor subunits and the postsynaptic density protein PSD-95. Science 269, 1737–1740 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Kim, E., Niethammer, M., Rothschild, A., Jan, Y. N. & Sheng, M. Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases. Nature 378, 85–88 (1995).

    Article  CAS  PubMed  Google Scholar 

  107. Zeng, M. et al. Reconstituted postsynaptic density as a molecular platform for understanding synapse formation and plasticity. Cell 174, 1172–1187 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. Brenman, J. E. et al. Interaction of nitric oxide synthase with the postsynaptic density protein PSD-95 and α1-syntrophin mediated by PDZ domains. Cell 84, 757–767 (1996).

    Article  CAS  PubMed  Google Scholar 

  109. Christopherson, K. S., Hillier, B. J., Lim, W. A. & Bredt, D. S. PSD-95 assembles a ternary complex with the N-methyl-D-aspartic acid receptor and a bivalent neuronal NO synthase PDZ domain. J. Biol. Chem. 274, 27467–27473 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Sattler, R. et al. Specific coupling of NMDA receptor activation to nitric oxide neurotoxicity by PSD-95 protein. Science 284, 1845–1848 (1999).

    Article  CAS  PubMed  Google Scholar 

  111. Luo, C. X. et al. Interaction of nNOS with PSD-95 negatively controls regenerative repair after stroke. J. Neurosci. 34, 13535–13548 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  112. Boissel, J. P., Bros, M., Schrock, A., Godtel-Armbrust, U. & Forstermann, U. Cyclic AMP-mediated upregulation of the expression of neuronal NO synthase in human A673 neuroepithelioma cells results in a decrease in the level of bioactive NO production: analysis of the signaling mechanisms that are involved. Biochemistry 43, 7197–7206 (2004).

    Article  CAS  PubMed  Google Scholar 

  113. Pou, S., Keaton, L., Surichamorn, W. & Rosen, G. M. Mechanism of superoxide generation by neuronal nitric-oxide synthase. J. Biol. Chem. 274, 9573–9580 (1999).

    Article  CAS  PubMed  Google Scholar 

  114. Schulz, J. B., Matthews, R. T., Klockgether, T., Dichgans, J. & Beal, M. F. The role of mitochondrial dysfunction and neuronal nitric oxide in animal models of neurodegenerative diseases. Mol. Cell. Biochem. 174, 193–197 (1997).

    Article  CAS  PubMed  Google Scholar 

  115. Grillo-Bosch, D., Choquet, D. & Sainlos, M. Inhibition of PDZ domain-mediated interactions. Drug Discov. Today Technol. 10, e531–e540 (2013).

    Article  PubMed  Google Scholar 

  116. Lapchak, P. A. & Zhang, J. H. Neuroprotective Therapy for Stroke and Ischemic Disease. 157-184 (Springer International Publishing, 2017).

  117. Ballarin, B. & Tymianski, M. Discovery and development of NA-1 for the treatment of acute ischemic stroke. Acta Pharmacol. Sin. 39, 661–668 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Florio, S. K. et al. Disruption of nNOS-PSD95 protein-protein interaction inhibits acute thermal hyperalgesia and chronic mechanical allodynia in rodents. Br. J. Pharmacol. 158, 494–506 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Zhou, L. et al. Treatment of cerebral ischemia by disrupting ischemia-induced interaction of nNOS with PSD-95. Nat. Med. 16, 1439–1443 (2010).

    Article  CAS  PubMed  Google Scholar 

  120. Bach, A. et al. Biochemical investigations of the mechanism of action of small molecules ZL006 and IC87201 as potential inhibitors of the nNOS-PDZ/PSD-95-PDZ interactions. Sci. Rep. 5, 12157 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Cui, H. et al. PDZ protein interactions underlying NMDA receptor-mediated excitotoxicity and neuroprotection by PSD-95 inhibitors. J. Neurosci. 27, 9901–9915 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Cook, D. J., Teves, L. & Tymianski, M. A translational paradigm for the preclinical evaluation of the stroke neuroprotectant Tat-NR2B9c in gyrencephalic nonhuman primates. Sci. Transl Med. 4, 154ra133 (2012).

    PubMed  Google Scholar 

  123. Cook, D. J., Teves, L. & Tymianski, M. Treatment of stroke with a PSD-95 inhibitor in the gyrencephalic primate brain. Nature 483, 213–217 (2012).

    Article  CAS  PubMed  Google Scholar 

  124. Hill, M. D. et al. Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 11, 942–950 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. US National Library of Medicine ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02930018 (2020).

  126. Hill, M. D. et al. Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial. Lancet 395, 878–887 (2020).

    Article  CAS  PubMed  Google Scholar 

  127. US National Library of Medicine ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02315443 (2019).

  128. Bach, A. et al. Modified peptides as potent inhibitors of the postsynaptic density-95/N-methyl-D-aspartate receptor interaction. J. Med. Chem. 51, 6450–6459 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Bach, A. et al. Design and synthesis of highly potent and plasma-stable dimeric inhibitors of the PSD-95-NMDA receptor interaction. Angew. Chem. Int. Ed. 48, 9685–9689 (2009).

    Article  CAS  Google Scholar 

  130. Bach, A. et al. Selectivity, efficacy and toxicity studies of UCCB01-144, a dimeric neuroprotective PSD-95 inhibitor. Neuropharmacology 150, 100–111 (2019).

    Article  CAS  PubMed  Google Scholar 

  131. Nissen, K. B. et al. Targeting protein-protein interactions with trimeric ligands: high affinity inhibitors of the MAGUK protein family. PLoS ONE 10, e0117668 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Nissen, K. B., Andersen, J. J., Haugaard-Kedstrom, L. M., Bach, A. & Stromgaard, K. Design, synthesis, and characterization of fatty acid derivatives of a dimeric peptide-based postsynaptic density-95 (PSD-95) inhibitor. J. Med. Chem. 58, 1575–1580 (2015).

    Article  CAS  PubMed  Google Scholar 

  133. Bard, L. et al. Dynamic and specific interaction between synaptic NR2-NMDA receptor and PDZ proteins. Proc. Natl Acad. Sci. USA 107, 19561–19566 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Sainlos, M. et al. Biomimetic divalent ligands for the acute disruption of synaptic AMPAR stabilization. Nat. Chem. Biol. 7, 81–91 (2011).

    Article  CAS  PubMed  Google Scholar 

  135. Rogawski, M. A. Revisiting AMPA receptors as an antiepileptic drug target. Epilepsy Curr. 11, 56–63 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Zwart, R. et al. Perampanel, an antagonist of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors, for the treatment of epilepsy: studies in human epileptic brain and nonepileptic brain and in rodent models. J. Pharmacol. Exp. Ther. 351, 124–133 (2014).

    Article  CAS  PubMed  Google Scholar 

  137. Rueter, S. M., Burns, C. M., Coode, S. A., Mookherjee, P. & Emeson, R. B. Glutamate receptor RNA editing in vitro by enzymatic conversion of adenosine to inosine. Science 267, 1491–1494 (1995).

    Article  CAS  PubMed  Google Scholar 

  138. Sommer, B. et al. Flip and flop: a cell-specific functional switch in glutamate-operated channels of the CNS. Science 249, 1580–1585 (1990).

    Article  CAS  PubMed  Google Scholar 

  139. Kato, A. S. et al. New transmembrane AMPA receptor regulatory protein isoform, gamma-7, differentially regulates AMPA receptors. J. Neurosci. 27, 4969–4977 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Kato, A. S., Siuda, E. R., Nisenbaum, E. S. & Bredt, D. S. AMPA receptor subunit-specific regulation by a distinct family of type II TARPs. Neuron 59, 986–996 (2008).

    Article  CAS  PubMed  Google Scholar 

  141. Kott, S., Werner, M., Korber, C. & Hollmann, M. Electrophysiological properties of AMPA receptors are differentially modulated depending on the associated member of the TARP family. J. Neurosci. 27, 3780–3789 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Cho, C. H., St-Gelais, F., Zhang, W., Tomita, S. & Howe, J. R. Two families of TARP isoforms that have distinct effects on the kinetic properties of AMPA receptors and synaptic currents. Neuron 55, 890–904 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Ravula, S. et al. Lead optimization of 5-aryl benzimidazolone- and oxindole-based AMPA receptor modulators selective for TARP gamma-8. ACS Med. Chem. Lett. 9, 821–826 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Savall, B. M. et al. Discovery of imidazo[1,2-a]pyrazines and pyrazolo[1,5-c]pyrimidines as TARP gamma-8 selective AMPAR negative modulators. ACS Med. Chem. Lett. 10, 267–272 (2019).

    Article  CAS  PubMed  Google Scholar 

  145. Knopp, K. L. et al. Modulation of TARP gamma8-containing AMPA receptors as a novel therapeutic approach for chronic pain. J. Pharmacol. Exp. Ther. 369, 345–363 (2019).

    Article  CAS  PubMed  Google Scholar 

  146. Chen, S. et al. Activation and desensitization mechanism of AMPA receptor-TARP complex by cryo-EM. Cell 170, 1234–1246 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lee, M. R. et al. Structural determinants of the gamma-8 TARP dependent AMPA receptor antagonist. ACS Chem. Neurosci. 8, 2631–2647 (2017).

    Article  CAS  PubMed  Google Scholar 

  148. von Engelhardt, J. et al. CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science 327, 1518–1522 (2010).

    Article  CAS  Google Scholar 

  149. Nakagawa, T. Structures of the AMPA receptor in complex with its auxiliary subunit cornichon. Science 366, 1259–1263 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Schwenk, J. & Fakler, B. Folding unpredicted. Science 366, 1194–1195 (2019).

    Article  CAS  PubMed  Google Scholar 

  151. Azumaya, C. M. et al. Screening for AMPA receptor auxiliary subunit specific modulators. PLoS ONE 12, e0174742 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  152. Staudinger, J., Zhou, J., Burgess, R., Elledge, S. J. & Olson, E. N. PICK1: a perinuclear binding protein and substrate for protein kinase C isolated by the yeast two-hybrid system. J. Cell Biol. 128, 263–271 (1995).

    Article  CAS  PubMed  Google Scholar 

  153. Thul, P. J. & Lindskog, C. The human protein atlas: a spatial map of the human proteome. Protein Sci. 27, 233–244 (2018).

    Article  CAS  PubMed  Google Scholar 

  154. Jaafari, N., Henley, J. M. & Hanley, J. G. PICK1 mediates transient synaptic expression of GluA2-lacking AMPA receptors during glycine-induced AMPA receptor trafficking. J. Neurosci. 32, 11618–11630 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Xia, J., Zhang, X., Staudinger, J. & Huganir, R. L. Clustering of AMPA receptors by the synaptic PDZ domain-containing protein PICK1. Neuron 22, 179–187 (1999).

    Article  CAS  PubMed  Google Scholar 

  156. Jensen, K. L. et al. PICK1-deficient mice exhibit impaired response to cocaine and dysregulated dopamine homeostasis. eNeuro https://doi.org/10.1523/ENEURO.0422-17.2018 (2018).

  157. Torres, G. E. The dopamine transporter proteome. J. Neurochem. 97, 3–10 (2006).

    Article  CAS  PubMed  Google Scholar 

  158. Torres, G. E. et al. Functional interaction between monoamine plasma membrane transporters and the synaptic PDZ domain-containing protein PICK1. Neuron 30, 121–134 (2001).

    Article  CAS  PubMed  Google Scholar 

  159. Li, Y. H., Zhang, N., Wang, Y. N., Shen, Y. & Wang, Y. Multiple faces of protein interacting with C kinase 1 (PICK1): Structure, function, and diseases. Neurochem. Int. 98, 115–121 (2016).

    Article  CAS  PubMed  Google Scholar 

  160. Thorsen, T. S. et al. A fluorescence polarization based screening assay for identification of small molecule inhibitors of the PICK1 PDZ domain. Comb. Chem. High. Throughput Screen. 14, 590–600 (2011).

    Article  CAS  PubMed  Google Scholar 

  161. Bach, A. et al. Structure-activity relationships of a small-molecule inhibitor of the PDZ domain of PICK1. Org. Biomol. Chem. 8, 4281–4288 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Thorsen, T. S. et al. Identification of a small-molecule inhibitor of the PICK1 PDZ domain that inhibits hippocampal LTP and LTD. Proc. Natl Acad. Sci. USA 107, 413–418 (2010).

    Article  CAS  PubMed  Google Scholar 

  163. Lin, E. Y. S. et al. Potent PDZ-domain PICK1 Inhibitors that modulate amyloid beta-mediated synaptic dysfunction. Sci. Rep. 8, 13438 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  164. Marcotte, D. J. et al. Lock and chop: a novel method for the generation of a PICK1 PDZ domain and piperidine-based inhibitor co-crystal structure. Protein Sci. 27, 672–680 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Alfonso, S. et al. Synapto-depressive effects of amyloid beta require PICK1. Eur. J. Neurosci. 39, 1225–1233 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  166. Daw, M. I. et al. PDZ proteins interacting with C-terminal GluR2/3 are involved in a PKC-dependent regulation of AMPA receptors at hippocampal synapses. Neuron 28, 873–886 (2000).

    Article  CAS  PubMed  Google Scholar 

  167. Famous, K. R. et al. Phosphorylation-dependent trafficking of GluR2-containing AMPA receptors in the nucleus accumbens plays a critical role in the reinstatement of cocaine seeking. J. Neurosci. 28, 11061–11070 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Garry, E. M. et al. Specific involvement in neuropathic pain of AMPA receptors and adapter proteins for the GluR2 subunit. Mol. Cell. Neurosci. 24, 10–22 (2003).

    Article  CAS  PubMed  Google Scholar 

  169. Rickhag, M. et al. Membrane-permeable C-terminal dopamine transporter peptides attenuate amphetamine-evoked dopamine release. J. Biol. Chem. 288, 27534–27544 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Christensen, N. R. et al. A high-affinity, bivalent PDZ domain inhibitor complexes PICK1 to alleviate neuropathic pain. EMBO Mol. Med. 12, e11248 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Schmid, C. L. et al. Bias factor and therapeutic window correlate to predict safer opioid analgesics. Cell 171, 1165–1175 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Campbell, A. P. & Smrcka, A. V. Targeting G protein-coupled receptor signalling by blocking G proteins. Nat. Rev. Drug Discov. 17, 789–803 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  173. Amara, S. G., Jonas, V., Rosenfeld, M. G., Ong, E. S. & Evans, R. M. Alternative RNA processing in calcitonin gene expression generates mRNAs encoding different polypeptide products. Nature 298, 240–244 (1982).

    Article  CAS  PubMed  Google Scholar 

  174. Goadsby, P. J., Edvinsson, L. & Ekman, R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann. Neurol. 28, 183–187 (1990).

    Article  CAS  PubMed  Google Scholar 

  175. Lassen, L. H. et al. CGRP may play a causative role in migraine. Cephalalgia 22, 54–61 (2002).

    Article  CAS  PubMed  Google Scholar 

  176. Hansen, J. M., Hauge, A. W., Olesen, J. & Ashina, M. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 30, 1179–1186 (2010).

    Article  PubMed  Google Scholar 

  177. Gonzalez-Hernandez, A., Marichal-Cancino, B. A., MaassenVanDenBrink, A. & Villalon, C. M. Side effects associated with current and prospective antimigraine pharmacotherapies. Expert. Opin. Drug Metab. Toxicol. 14, 25–41 (2018).

    Article  CAS  PubMed  Google Scholar 

  178. Burch, R. C., Loder, S., Loder, E. & Smitherman, T. A. The prevalence and burden of migraine and severe headache in the United States: updated statistics from government health surveillance studies. Headache 55, 21–34 (2015).

    Article  PubMed  Google Scholar 

  179. McLatchie, L. M. et al. RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature 393, 333–339 (1998).

    Article  CAS  PubMed  Google Scholar 

  180. Gingell, J. J., Hendrikse, E. R. & Hay, D. L. New insights into the regulation of CGRP-family receptors. Trends Pharmacol. Sci. 40, 71–83 (2019).

    Article  CAS  PubMed  Google Scholar 

  181. Hay, D. L. & Pioszak, A. A. Receptor activity-modifying proteins (RAMPs): new insights and roles. Annu. Rev. Pharmacol. Toxicol. 56, 469–487 (2016).

    Article  CAS  PubMed  Google Scholar 

  182. Shi, L. et al. Pharmacologic characterization of AMG 334, a potent and selective human monoclonal antibody against the calcitonin gene-related peptide receptor. J. Pharmacol. Exp. Ther. 356, 223–231 (2016). This study characterizes erenumab, the first mAb that targets the CALCRL–RAMP1 complex.

    Article  CAS  PubMed  Google Scholar 

  183. Evans, B. N., Rosenblatt, M. I., Mnayer, L. O., Oliver, K. R. & Dickerson, I. M. CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors. J. Biol. Chem. 275, 31438–31443 (2000).

    Article  CAS  PubMed  Google Scholar 

  184. Egea, S. C. & Dickerson, I. M. Direct interactions between calcitonin-like receptor (CLR) and CGRP-receptor component protein (RCP) regulate CGRP receptor signaling. Endocrinology 153, 1850–1860 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Dickerson, I. Role of CGRP-receptor component protein (RCP) in CLR/RAMP function. Curr. Protein Peptide Sci. 14, 407–415 (2013).

    Article  CAS  Google Scholar 

  186. Liang, Y. L. et al. Cryo-EM structure of the active, Gs-protein complexed, human CGRP receptor. Nature 561, 492–497 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Schuster, N. M. & Rapoport, A. M. Calcitonin gene-related peptide-targeted therapies for migraine and cluster headache: a review. Clin. Neuropharmacol. 40, 169–174 (2017).

    Article  CAS  PubMed  Google Scholar 

  188. Goadsby, P. J. et al. A controlled trial of erenumab for episodic migraine. N. Engl. J. Med. 377, 2123–2132 (2017).

    Article  CAS  PubMed  Google Scholar 

  189. Tepper, S. J. Anti-calcitonin gene-related peptide (CGRP) therapies: update on a previous review after the American Headache Society 60th Scientific Meeting, San Francisco, June 2018. Headache 58, 276–290 (2018).

    Article  PubMed  Google Scholar 

  190. Tepper, S. J. History and review of anti-calcitonin gene-related peptide (CGRP) therapies: from translational research to treatment. Headache 58, 238–275 (2018).

    Article  PubMed  Google Scholar 

  191. Mullard, A. 2018 FDA drug approvals. Nat. Rev. Drug Discov. 18, 85–89 (2019).

    Article  PubMed  Google Scholar 

  192. Silberstein, S. D. et al. Fremanezumab for the preventive treatment of chronic migraine. N. Engl. J. Med. 377, 2113–2122 (2017).

    Article  CAS  PubMed  Google Scholar 

  193. Dodick, D. W. et al. Safety and efficacy of LY2951742, a monoclonal antibody to calcitonin gene-related peptide, for the prevention of migraine: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Neurol. 13, 885–892 (2014).

    Article  CAS  PubMed  Google Scholar 

  194. Dodick, D. W. et al. Safety and efficacy of ALD403, an antibody to calcitonin gene-related peptide, for the prevention of frequent episodic migraine: a randomised, double-blind, placebo-controlled, exploratory phase 2 trial. Lancet Neurol. 13, 1100–1107 (2014).

    Article  CAS  PubMed  Google Scholar 

  195. US Food and Drug Administration. Vyepti: FDA-Approved Drugs https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=761119 (2020).

  196. Edvinsson, L. The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache 57, 47–55 (2017).

    Article  PubMed  Google Scholar 

  197. Doods, H. et al. Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br. J. Pharmacol. 129, 420–423 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Ho, T. W. et al. Efficacy and tolerability of MK-0974 (telcagepant), a new oral antagonist of calcitonin gene-related peptide receptor, compared with zolmitriptan for acute migraine: a randomised, placebo-controlled, parallel-treatment trial. Lancet 372, 2115–2123 (2008).

    Article  CAS  PubMed  Google Scholar 

  199. Voss, T. et al. A phase IIb randomized, double-blind, placebo-controlled trial of ubrogepant for the acute treatment of migraine. Cephalalgia 36, 887–898 (2016).

    Article  PubMed  Google Scholar 

  200. Negro, A. & Martelletti, P. Gepants for the treatment of migraine. Expert Opin. Investig. Drugs 28, 555–567 (2019).

    Article  CAS  PubMed  Google Scholar 

  201. US Food and Drug Administration. Ubrelvy: FDA-Approved Drugs https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=211765 (2019).

  202. Marcus, R. et al. BMS-927711 for the acute treatment of migraine: a double-blind, randomized, placebo controlled, dose-ranging trial. Cephalalgia 34, 114–125 (2013).

    Article  PubMed  Google Scholar 

  203. US Food and Drug Administration Nurtec ODT: FDA-Approved Drugs https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=212728 (2020).

  204. Hay, D. L., Garelja, M. L., Poyner, D. R. & Walker, C. S. Update on the pharmacology of calcitonin/CGRP family of peptides: IUPHAR review 25. Br. J. Pharmacol. 175, 3–17 (2018).

    Article  CAS  PubMed  Google Scholar 

  205. Bowery, N. G. GABAB receptor: a site of therapeutic benefit. Curr. Opin. Pharmacol. 6, 37–43 (2006).

    Article  CAS  PubMed  Google Scholar 

  206. Froestl, W. Chemistry and pharmacology of GABAB receptor ligands. Adv. Pharmacol. 58, 19–62 (2010).

    Article  CAS  PubMed  Google Scholar 

  207. Gassmann, M. & Bettler, B. Regulation of neuronal GABAB receptor functions by subunit composition. Nat. Rev. Neurosci. 13, 380–394 (2012).

    Article  CAS  PubMed  Google Scholar 

  208. Turecek, R. et al. Auxiliary GABAB receptor subunits uncouple G protein βγ subunits from effector channels to induce desensitization. Neuron 82, 1032–1044 (2014).

    Article  CAS  PubMed  Google Scholar 

  209. Bettler, B. & Fakler, B. Ionotropic AMPA-type glutamate and metabotropic GABAB receptors: determining cellular physiology by proteomes. Curr. Opin. Neurobiol. 45, 16–23 (2017).

    Article  CAS  PubMed  Google Scholar 

  210. Zheng, S., Abreu, N., Levitz, J. & Kruse, A. C. Structural basis for KCTD-mediated rapid desensitization of GABAB signalling. Nature 567, 127–131 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Zuo, H. et al. Structural basis for auxiliary subunit KCTD16 regulation of the GABAB receptor. Proc. Natl Acad. Sci. USA 116, 8370–8379 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Metz, M., Gassmann, M., Fakler, B., Schaeren-Wiemers, N. & Bettler, B. Distribution of the auxiliary GABAB receptor subunits KCTD8, 12, 12b, and 16 in the mouse brain. J. Comp. Neurol. 519, 1435–1454 (2011).

    Article  CAS  PubMed  Google Scholar 

  213. Fritzius, T. & Bettler, B. The organizing principle of GABAB receptor complexes: Physiological and pharmacological implications. Basic Clin. Pharmacol. Toxicol. https://doi.org/10.1111/bcpt.13241 (2019).

  214. Sibille, E. et al. A molecular signature of depression in the amygdala. Am. J. Psychiatry 166, 1011–1024 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  215. Lee, M. T. et al. Genome-wide association study of bipolar I disorder in the Han Chinese population. Mol. Psychiatry 16, 548–556 (2011).

    Article  CAS  PubMed  Google Scholar 

  216. Booker, S. A. et al. KCTD12 auxiliary proteins modulate kinetics of GABAB receptor-mediated inhibition in cholecystokinin-containing interneurons. Cereb. Cortex 27, 2318–2334 (2017).

    PubMed  Google Scholar 

  217. Cathomas, F. et al. Altered emotionality and neuronal excitability in mice lacking KCTD12, an auxiliary subunit of GABAB receptors associated with mood disorders. Transl. Psychiatry 5, e510 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Sereikaite, V. et al. Targeting the gamma-aminobutyric acid type B (GABAB) receptor complex: development of inhibitors targeting the K+ channel tetramerization domain (KCTD) containing proteins/GABAB receptor protein-protein interaction. J. Med. Chem. 62, 8819–8830 (2019). This article reports the first tool compound that binds to auxiliary KCTD subunits of GABAB receptors.

    Article  CAS  PubMed  Google Scholar 

  219. Rice, H. C. et al. Secreted amyloid-beta precursor protein functions as a GABABR1a ligand to modulate synaptic transmission. Science 363, eaao4827 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Dinamarca, M. C. et al. Complex formation of APP with GABAB receptors links axonal trafficking to amyloidogenic processing. Nat. Commun. 10, 1331 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Rouault, A. A. J., Srinivasan, D. K., Yin, T. C., Lee, A. A. & Sebag, J. A. Melanocortin receptor accessory proteins (MRAPs): Functions in the melanocortin system and beyond. Biochim. Biophys. Acta Mol. Basis Dis. 1863, 2462–2467 (2017).

    Article  CAS  PubMed  Google Scholar 

  222. Baron, M. et al. Loss-of-function mutations in MRAP2 are pathogenic in hyperphagic obesity with hyperglycemia and hypertension. Nat. Med. 25, 1733–1738 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Andrei, S. A. et al. Stabilization of protein-protein interactions in drug discovery. Expert Opin. Drug Discov. 12, 925–940 (2017).

    Article  CAS  PubMed  Google Scholar 

  224. Arkin, M. R., Tang, Y. & Wells, J. A. Small-molecule inhibitors of protein-protein interactions: progressing toward the reality. Chem. Biol. 21, 1102–1114 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Manglik, A., Kobilka, B. K. & Steyaert, J. Nanobodies to study G protein-coupled receptor structure and function. Annu. Rev. Pharmacol. Toxicol. 57, 19–37 (2017).

    Article  CAS  PubMed  Google Scholar 

  226. Burslem, G. M. et al. The advantages of targeted protein degradation over inhibition: an RTK case study. Cell Chem. Biol. 25, 67–77 (2018).

    Article  CAS  PubMed  Google Scholar 

  227. Bensimon, A. et al. Targeted degradation of SLC transporters reveals amenability of multi-pass transmembrane proteins to ligand-induced proteolysis. Cell Chem. Biol. 27, 728–739 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Field, M. J. et al. Identification of the alpha2-delta-1 subunit of voltage-dependent calcium channels as a molecular target for pain mediating the analgesic actions of pregabalin. Proc. Natl Acad. Sci. USA 103, 17537–17542 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Modell, A. E., Blosser, S. L. & Arora, P. S. Systematic targeting of protein-protein interactions. Trends Pharmacol. Sci. 37, 702–713 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Wasko, M. J., Pellegrene, K. A., Madura, J. D. & Surratt, C. K. A role for fragment-based drug design in developing novel lead compounds for central nervous system targets. Front. Neurol. 6, 197 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  231. Hillier, B. J. Unexpected modes of PDZ domain scaffolding revealed by structure of nNOS-syntrophin complex. Science 284, 812–815 (1999).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Center for Biopharmaceuticals, Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark

    Mette Ishøy Rosenbaum, Louise S. Clemmensen & Kristian Strømgaard

  2. Neuroscience Discovery, Janssen Pharmaceutical Companies of Johnson & Johnson, San Diego, CA, USA

    David S. Bredt

  3. Department of Biomedicine, University of Basel, Basel, Switzerland

    Bernhard Bettler

Authors
  1. Mette Ishøy Rosenbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Louise S. Clemmensen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. David S. Bredt
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bernhard Bettler
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kristian Strømgaard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kristian Strømgaard.

Ethics declarations

Competing interests

M.I.R. is a full-time employee of Novo Nordisk at the time of publication. K.S. is a co-founder and a part-time employee of Avilex Pharma. B.B. is a member of the scientific advisory board of Addex Therapeutics, Geneva. L.S.C. is a full-time employee of BioInnovation Institute. D.S.B. is a full-time employee of Janssen Pharmaceuticals.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Glossary

Blood–brain barrier

The blood–brain barrier strictly restricts which molecules can enter the brain, and it comprises tight junctions between endothelial cells, astrocytic endfeet and a basement membrane.

Scaffolding protein

A protein that organizes multiple proteins into a functional protein complex.

Desensitization

A mechanism that uncouples downstream receptor signalling during prolonged activation to attenuate the excessive cellular effects.

Phenotypic drug discovery

A screening method to identify compounds with desired biological phenotypes that is agnostic of the molecular target.

DNA-encoded chemical libraries

(DELs). Large collections of small molecules (up to 109) whose structure is connected to a unique DNA sequence, allowing pooled screening. Sequencing of screening hits subsequently allows chemical identification.

Targeted protein degradation

A technology that targets a protein of interest for degradation by using the cellular degradation machinery, such as the ubiquitin–proteasome system.

Cell-penetrating peptides

Short peptide sequences that promote the cellular uptake of various cargoes, such as peptides, proteins and oligonucleotides.

Excitotoxicity

A process in which neurons are damaged owing to excessive activation of glutamate receptors.

Functional proteomics

A proteomic approach that aims to elucidate and identify interacting proteins of stable protein complexes.

Biased signalling

A concept of receptor modulation that allows selective pharmacological activation of one downstream signalling pathway over others.

Nootropic effects

A general term that describes improved cognitive functions.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rosenbaum, M.I., Clemmensen, L.S., Bredt, D.S. et al. Targeting receptor complexes: a new dimension in drug discovery. Nat Rev Drug Discov 19, 884–901 (2020). https://doi.org/10.1038/s41573-020-0086-4

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41573-020-0086-4

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing