Development and applications of photoswitchable muscarinic ligands
- Autores: Fabio Riefolo
- Directores de la Tesis: Pau Gorostiza Langa (dir. tes.)
- Lectura: En la Universitat de Barcelona ( España ) en 2020
- Idioma: español
- Tribunal Calificador de la Tesis: Martin Lohse (presid.), Diego Muñoz-Torrero López-Ibarra (secret.), Ma. Angel Lanuza Escolano (voc.)
- Programa de doctorado: Programa de Doctorado en Química Orgánica por la Universidad de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TESEO
- Resumen
Muscarinic acetylcholine receptors (mAChRs) are five (M1-M5) and belong to the class A GPCRs, modulating numerous central and peripheral physiological responses. Muscarinic drugs can be very effective for many therapies such as for cognitive disorders and heart disease, but their full potential is not yet been achieved in medicine because of their low subtype selectivity and undeniable side effects. Photopharmacology is based on reversible photoisomerisable drugs that can be controlled with light over the body, dramatically improving their selectivity for a target expressed in a specific location and reducing the side effects to the minimal expression. In order to introduce alternatives for improving the specificity of muscarinic drugs, we rational design and develop light-regulated ligands that can enable the optical modulation of muscarinic receptors and the physiological processes in which they are involved. We developed different light-sensitive derivatives of Iperoxo, a very potent muscarinic agonist. Among the others, the Iperoxo derivative named PAI turned out to be a potent photoswitchable activator of M2 receptors. This compound demonstrates to modulate the cardiac function with light in vivo in different wild type animal models, standing as a potential alternative for classical antiarrhythmic drugs that cannot be manipulated spatiotemporally. Moreover, the administration of PAI in the central nervous system (isolated cortical slices and in anesthetized living mice) can manipulate brain state transitions with light, a function that bears high therapeutic interest in several neurological disorders. Under two-photon excitation, PAI is sensible to near-infrared light (840 nm), which can deeply penetrate biological tissues with reduced damages, opening the way to noninvasive applications in vivo. Because of their therapeutic relevance, we also developed photoswitchable derivatives of the tricyclic M1 antagonist pirenzepine. We designed the new “crypto-azologization” strategy by replacing the heterotricyclic system of pirenzepine with different azobenzene scaffolds. This strategy was effectively validated by light-controlling M1 receptors inhibition in cardiac atria ex vivo. This “crypto-azologization” strategy has the potential to be used for controlling the action of many other mainstream tricyclic drugs with light.
