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    Precise spatiotemporal control of GPCR receptors with light and photoactive ligands



    Amadeu Llebaria 

    Amadeu Llebaria

    MCS, Laboratory of Medicinal Chemistry & Synthesis,
    Institute for Advanced Chemistry of Catalonia, Barcelona, Spain


    Lundi 22 mai 2017 à 14h00


     invité par Ralf Jockers


    Institut Cochin, 22 rue Méchain, 75014 Paris
    Salle de réunion Méchain 1, 1er étage

    The administration of a photocontrolled ligand in combination with illumination that is patterned in space and time can provide a novel degree of control and regulation of receptor activity. This method would allow precisely focusing the action of the ligand, controlling the location and the temporal extension of its effects.

    We have recently developed light-regulated allosteric modulators for  metabotropic glutamate receptors (mGluRs). These include Alloswitch-11 and related phenylazopyridines with NAM activity in mGlu5 and OptoGluNAM4.1, the first mGlu4 NAM active in vivo2. These photopharmacological tools are based in photoswitchable azobenzene scaffolds, which show a robust activity dependent of the illumination conditions allowing the real-time regulation of the intracellular effects of these GPCRs in cells. In vivo the compounds trigger light dependent behavioral effects in zebra fish embryos, tadpoles and rodents, including some pain models.

    We have shown that localized (in)activation of endogenous receptors with light in the amygdala of live mice results in a control of  chronic pain.4  Illuminating a mGlu4 photoswitchable ligand in the brain  rapidly  and reversibly inhibits chronic pain behavioral symptoms while measuring the painful response in the periphery. We have demonstrated a photopharmacological dynamic regulation of sensory and emotional information, bypassing central pain sensitization processes established for long periods of time and validated a local mGlu4  as a target receptor for persistent pain. Finally we have shown that we can use photodelivery for drug  can induce a light and tissue dependent  analgesic effect in mice.5


    1. Pittolo S, et al. (2014) Nat Chem Biol.10:813-5
    2. Rovira X et al  (2016) Cell Chem Biol. 23):929-34
    3. Gómez-Santacana X et al ACS Cent Sci (2016 ) Dec 19, DOI:10.1021/acscentsci.6b00353
    4. Zussy C, et al. Mol Psychiatry (2016) Dec 20. doi: 10.1038/mp.2016.223.
    5. Font, J, et al eLife (2017), 6:e23545.


    Amadeu Llebaria is chemist and has been working in design and synthesis of organic molecules, medicinal chemistry and chemical biology both in basic science and industrial applications. He is now interested in the development of radically new approaches for drug therapeutics. Working in the borderline of chemistry, biology and biophysics he is involved in glycolipid immunotherapeutics, chemical methods for endogenous protein labelling and the use of light for controlling the activity of proteins and receptors by photoswitchable ligands.  


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