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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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.).
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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.
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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.
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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)
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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DOI: https://doi.org/10.1038/nchembio.1612
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