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An allosteric modulator to control endogenous G protein-coupled receptors with light

Nature Chemical Biology volume 10, pages 813–815 (2014)Cite this article

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Abstract

Controlling drug activity with light offers the possibility of enhancing pharmacological selectivity with spatial and temporal regulation, thus enabling highly localized therapeutic effects and precise dosing patterns. Here we report on the development and characterization of what is to our knowledge the first photoswitchable allosteric modulator of a G protein–coupled receptor. Alloswitch-1 is selective for the metabotropic glutamate receptor mGlu5 and enables the optical control of endogenous mGlu5 receptors.

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Figure 1: Design strategy and optochemical properties of alloswitch-1.
Figure 2: Alloswitch-1 optically modulates mGlu5 in vitro and allows optical control of behavior in X. tropicalis tadpoles.

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References

  1. Langer, R. Nature 392, 5–10 (1998).

    CAS  PubMed  Google Scholar 

  2. Wenthur, C.J., Gentry, P.R., Mathews, T.P. & Lindsley, C.W. Annu. Rev. Pharmacol. Toxicol. 54, 165–184 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Miller, G. Science 329, 502–504 (2010).

    Article  CAS  PubMed  Google Scholar 

  4. Rajendran, L., Knölker, H.J. & Simons, K. Nat. Rev. Drug Discov. 9, 29–42 (2010).

    Article  CAS  PubMed  Google Scholar 

  5. Timko, B.P., Dvir, T. & Kohane, D.S. Adv. Mater. 22, 4925–4943 (2010).

    Article  CAS  PubMed  Google Scholar 

  6. Gorostiza, P. & Isacoff, E.Y. Science 322, 395–399 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Kramer, R.H., Mourot, A. & Adesnik, H. Nat. Neurosci. 16, 816–823 (2013).

    PubMed  PubMed Central  Google Scholar 

  8. Nevola, L. et al. Angew. Chem. Int. Edn Engl. 52, 7704–7708 (2013).

    Article  CAS  Google Scholar 

  9. Hopkins, A.L. & Groom, C.R. Nat. Rev. Drug Discov. 1, 727–730 (2002).

    Article  CAS  PubMed  Google Scholar 

  10. Conn, P.J., Christopoulos, A. & Lindsley, C.W. Nat. Rev. Drug Discov. 8, 41–54 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Nicoletti, F. et al. Neuropharmacology 60, 1017–1041 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Bartels, E., Wassermann, N.H. & Erlanger, B.F. Proc. Natl. Acad. Sci. USA 68, 1820–1823 (1971).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Volgraf, M. et al. J. Am. Chem. Soc. 129, 260–261 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Banghart, M.R. et al. Angew. Chem. Int. Edn Engl. 48, 9097–9101 (2009).

    Article  CAS  Google Scholar 

  15. Mourot, A. et al. Nat. Methods 9, 396–402 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Stein, M. et al. Angew. Chem. Int. Edn Engl. 51, 10500–10504 (2012).

    Article  CAS  Google Scholar 

  17. Stein, M., Breit, A., Fehrentz, T., Gudermann, T. & Trauner, D. Angew. Chem. Int. Edn Engl. 52, 9845–9848 (2013).

    Article  CAS  Google Scholar 

  18. Reiter, A., Skerra, A., Trauner, D. & Schiefner, A. Biochemistry 52, 8972–8974 (2013).

    Article  CAS  PubMed  Google Scholar 

  19. Wood, M.R., Hopkins, C.R., Brogan, J.T., Conn, P.J. & Lindsley, C.W. Biochemistry 50, 2403–2410 (2011).

    Article  CAS  PubMed  Google Scholar 

  20. Ghose, A.K., Herbertz, T., Hudkins, R.L., Dorsey, B.D. & Mallamo, J.P. ACS Chem. Neurosci. 3, 50–68 (2012).

    Article  CAS  PubMed  Google Scholar 

  21. Engers, D.W. et al. J. Med. Chem. 54, 1106–1110 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Gregory, K.J., Noetzel, M.J. & Niswender, C.M. in Progress in Molecular Biology and Translational Science, Vol. 115 (ed. Terry, K.) 61–121 (Academic Press, 2013).

  23. Mathiesen, J.M., Svendsen, N., Bräuner-Osborne, H., Thomsen, C. & Ramirez, M.T. Br. J. Pharmacol. 138, 1026–1030 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Masseck, O.A., Rubelowski, J.M., Spoida, K. & Herlitze, S. Exp. Physiol. 96, 51–56 (2011).

    Article  CAS  PubMed  Google Scholar 

  25. Levitz, J. et al. Nat. Neurosci. 16, 507–516 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Brabet, I. et al. Neuropharmacology 37, 1043–1051 (1998).

    Article  CAS  PubMed  Google Scholar 

  27. Gomeza, J. et al. Mol. Pharmacol. 50, 923–930 (1996).

    CAS  PubMed  Google Scholar 

  28. Miller, S., Romano, C. & Cotman, C.W. J. Neurosci. 15, 6103–6109 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Kawabata, S. et al. Nature 383, 89–92 (1996).

    Article  CAS  PubMed  Google Scholar 

  30. Nash, M.S. et al. J. Biol. Chem. 277, 35947–35960 (2002).

    Article  CAS  PubMed  Google Scholar 

  31. Nieuwkoop, P.D. & Faber, J. Normal table of Xenopus laevis (Daudin) (North-Holland Publishing, Amsterdam, 1975).

  32. Ango, F. et al. Neuropharmacology 38, 793–803 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Benjamini, Y. & Hochberg, Y. J. R. Stat. Soc. Ser. A Stat. Soc. 57, 289–300 (1995).

    Google Scholar 

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Acknowledgements

We are grateful to C. Serra, R. Pérez-Gregorio and L. Muñoz for synthetic and analytical support; F. Malhaire for technical support in cell-based pharmacological assays; Y. Pérez for NMR support; and H. Masanas and B. Terni for animal care and natural matings. We thank the Center for Scientific and Academic Services of Catalonia (CESCA) for the use of their facilities. The Pt-Fe catalyst used in the synthesis was a kind gift of Evonik Industries AG (Germany). We are also grateful to F. Ciruela, M. Izquierdo-Serra, F. Aguado and M.J. Bleda for helpful discussions. We acknowledge financial support from the RecerCaixa foundation (2010ACUP00378 to P.G., J.G. and A. Llebaria); the Marató de TV3 Foundation (110230 to J.G., 110231 to A. Llebaria, 110232 to C.G., 111531 to A. Llobet and P.G.); the Human Frontier Science Program (CDA022/2006 to P.G.); the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreements 270483 (Focus), 210355 (Opticalbullet) and 335011 (Theralight) to P.G.; the Federation of European Biochemical Societies; the Catalan government (2010 BP-A 00194 to X.R., 2012FI_B 01122 to S.P., 2012 CTP 00033 and 2012 BE1 00597 to X.G.-S., 2014SGR-1251 to P.G. and 2009SGR-1072 to A. Llebaria); the Spanish Government (CTQ2008-06160, SAF2010-19257, SAF2012-36375 and CTQ2013-43892R to P.G.); and the ERANET Neuron LIGHTPAIN project (to A. Llebaria, J.G. and J.-P.P.).

Author information

Author notes

  1. Silvia Pittolo and Xavier Gómez-Santacana: These authors contributed equally to this work.

  2. Amadeu Llebaria and Pau Gorostiza: These authors jointly directed this work.

Authors and Affiliations

  1. Institute for Bioengineering of Catalonia (IBEC), Barcelona, Spain

    Silvia Pittolo, Xavier Gómez-Santacana, Kay Eckelt & Pau Gorostiza

  2. Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Barcelona, Spain

    Xavier Gómez-Santacana & Amadeu Llebaria

  3. Institut de Neurociències and Unitat de Bioestadística, Universitat Autònoma de Barcelona, Bellaterra, Spain

    Xavier Gómez-Santacana, Xavier Rovira, James Dalton & Jesús Giraldo

  4. Network Biomedical Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Zaragoza, Spain

    Kay Eckelt & Pau Gorostiza

  5. Institut de Génomique Fonctionnelle, CNRS, UMR-5203, Université de Montpellier, Montpellier, France

    Xavier Rovira, Cyril Goudet & Jean-Philippe Pin

  6. INSERM, U661, F-34000, Montpellier, France

    Xavier Rovira, Cyril Goudet & Jean-Philippe Pin

  7. Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain

    Artur Llobet

  8. Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain

    Pau Gorostiza

Authors
  1. Silvia Pittolo
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Contributions

S.P. performed and analyzed single-cell photoswitching and pharmacological assays, characterized compound photoisomerization and wrote the paper. X.G.-S. designed and synthesized the compounds, characterized photoisomerization, performed pharmacological assays and wrote the paper. K.E. performed animal experiments, analyzed animal activity data and wrote the paper. X.R. designed compounds and performed pharmacological assays. J.D. designed compounds. C.G. and J.-P.P analyzed pharmacological results. A. Llobet designed experiments and analyzed animal activity data. J.G. designed experiments, analyzed data and designed compounds. A. Llebaria conceived and supervised the project, designed experiments, designed compounds, analyzed data and wrote the paper. P.G. conceived and supervised the project, designed experiments, analyzed data and wrote the paper. All of the authors made corrections to the manuscript.

Corresponding authors

Correspondence to Amadeu Llebaria or Pau Gorostiza.

Ethics declarations

Competing interests

A. Llebaria, P.G., J.G., X.G.-S., S.P., X.R., C.G. and J.-P.P. have filed a patent application for photochromic allosteric modulators of mGlu receptors.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Table 1 and Supplementary Figures 1–13. (PDF 9773 kb)

Supplementary Note

Experimental procedures and data for synthesis and characterization of compounds 2 and 3 are displayed in the Supplementary Note file. (PDF 5058 kb)

Effect of Alloswitch-1 on tadpoles' motility in different light conditions. (MOV 15401 kb)

Effect of Fenobam on tadpoles' motility in different light conditions. (MOV 21038 kb)

Supplementary Data Set 1

Results of the ExpresSProfile performed at Cerep (Poitiers, France). (XLS 35 kb)

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Pittolo, S., Gómez-Santacana, X., Eckelt, K. et al. An allosteric modulator to control endogenous G protein-coupled receptors with light. Nat Chem Biol 10, 813–815 (2014). https://doi.org/10.1038/nchembio.1612

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