Advanced synthetic strategies to control pharmacological action using ultraviolet, visible, and infrared light

[eng] Photopharmacology fuses the best features of various neuromodulation techniques, allowing high spatial and temporal control to overcome the adverse effects of systemic pharmacology. The control of neuronal activity with photopharmacology can be achieved by (1) freely diffusible ligands that exert different pharmacological actions in the dark and with light, (2) photoswitchable molecules covalently bound to their receptors that allow a more selective action, with high precision and control of a specific neuronal population, and (3) the release of active ligands by light-controlled drug encapsulation systems. In this thesis, we have used these three design strategies to neuromodulate different targets. In the first part, we have focused on photopharmacology based on ultraviolet and visible light. First, we have developed photochromic glycine receptor ligand analogues to expand the active molecules available for this class of orphan receptors, study glycinergic transmission and potentially inhibit neuropathic pain with light. We have also used ultraviolet light to trigger the selective release of glutamatergic and muscarinic ligands from supramolecular polymer-based drug encapsulation systems. We have designed two different strategies to encapsulate drugs. With the former, we have obtained good molecular coupling results using transmission electron microscopy and circular dichroism, but we have not been able to verify its efficacy in biological systems due to the low solubility of the polymer. We have overcome this barrier in the second strategy, introducing a potent muscarinic agonist into the supramolecular structure and demonstrating its release using the calcium imaging technique. In this way, we have demonstrated the applicability of this class of supramolecular polymers as selective light-activated drug delivery systems. Despite the great technical advances achieved over the last twenty years, the translation of photopharmacology to the clinic remains difficult, partly due to the toxicity and low tissue penetration of ultraviolet light. For this reason, in the second part of this thesis, we have developed photopharmacological ligands that allow the application of light more deeply and safely. First, we used two-photon excitation to control neuronal activation by means of a novel photoswitchable ligand that can covalently conjugate to native ionotropic glutamate receptors, without requiring mutagenesis. In addition, this new ligand has shown selectivity for specific subtypes of ionotropic glutamate receptors, AMPA and kainate receptors. Activation with near-infrared light by multiphoton stimulation also offers focused stimulation at the micrometer scale and in three dimensions. However, the technical complexity of multiphotonic stimulation limits its clinical applications to practice. Therefore, we have also developed photochromic ligands based on donor and acceptor Stenhouse adductes that can be photoactivated in the therapeutic window of the spectrum by excitation of a photon. These new ligands contain active barbiturates at gamma-aminobutyric acid receptors and chemical substitutions that push their absorption at infrared wavelengths. We have also studied their isomerization mechanisms to understand how to make them compatible with protic environments. The most promising compound in the library has good solubility, absorption wavelength in dark red, and antagonist activity at gamma-aminobutyric acid receptors.