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Synthesis and mode of action of photoswitchable ligands for neuromodulation

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Universitat de Barcelona. Facultat de Farmàcia i Ciències de l'Alimentació

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[eng] My thesis was part of a collaborative project at the interface of neuropharmacology and medicinal chemistry that aimed to better understand the neuromodulation mechanisms associated with Alzheimer’s Disease (AD). In this context, my role was to develop photo- controllable ligands targeting two GPCRs known to be involved in this disease: the main target of the project was mGlu5 and A2AR was a subsidiary target. In addition to their involvement in AD and others neurodegenerative diseases, mGlu5 and A2A receptors are also drug targets of interest in a wider range of therapeutic areas, from pain to cancer. Photoswitchable ligands provide a high degree of spatiotemporal control of the ligand activity by using light as an external stimulus that could greatly facilitate the unraveling of the downstream mechanisms that lead to the pathology. Furthermore, in addition to their use in fundamental research, they may also offer unique advantages for clinical research in the future.
Along this thesis, the following specific objectives were pursued:
I.	To explore the light sensitivity of clinical drug istradefylline (106) and its potential applicability in photopharmacology as a photoinactivatable A2AR antagonist. A full characterization of the molecular mechanisms underlying istradefylline photosensitivity and its use in pilot dynamic photopharmacological experiments in cellulo and in vivo are presented in chapter 1.

II.	To develop the first selective A2AR photoswitchable antagonist using istradefylline and related molecules as scaffold for the azologization process. The molecular design and the photochemical and photopharmacological characterization of three series of compounds are described in chapter 2. Additionally, an in vivo proof of concept of the use of one of these ligands in the context of chronic pain is reported.

III.	To obtain the first mGlu5 positive allosteric modulators (PAM) derived from the scaffolds of the two potent mGlu5 PAM VU0424465 (118) and VU0403602 (119) by an azologization process. The molecular design and the photochemical and photopharmacological characterization of these two photoswitchable compounds are described in chapter 3.

IV.	To develop a new generation of photoswitchable mGlu5 negative allosteric modulators (NAM) with light-on properties (i.e. inactive ligands in the dark that are switched-on at a specific wavelenght) using the recent strategy of ‘sign inversion’. The general design along with the photochemical and photopharmacological properties of a first series of ligands are presented in chapter 4. In addition, a comparison of the photopharmacological properties of our new ligands and the previously developed light-off mGlu5 NAM alloswitch-1 (69) in cells and in zebrafish are shown. Finally, the first results obtained by our collaborators using these new light-on ligands in a mouse model of Alzheimer's disease will be presented.

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Tesis Doctorals - Facultat - Farmàcia i Ciències de l'Alimentació

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Synthesis and mode of action of photoswitchable ligands for neuromodulation