Resumen de New photopharmacological tools for the light induced control of neuronal signalling
The main objective of neuroscience is the study and control of neuronal systems. Nowadays, this area is being revolutionised by the use of photoresponsive small molecules, a field known as photopharmacology. By enabling remote activation of drugs with light, photopharmacology seeks to tackle some of the main challenges faced by conventional pharmacology, such as poor drug selectivity and side effects.[1] Three main strategies have been derived in this area: photocaged ligands (CL), freely diffusing prodrugs the effect of which is triggered by removing photolabile protecting groups upon illumination; photochromic ligands (PCL), which allow reversible modulation of the response of bioactive molecules through photoisomerisation of appended light-responsive moieties; and photoswitched tethered ligands (PTL), a special case of PCLs that are covalently attached to the therapeutic receptor. [1,2] Although these approaches have proven to be successful for a variety of therapeutic targets in vitro and in vivo, several challenges still remain in the field of photopharmacology. Therefore, in this work we have aimed at the investigation of new photopharmacological strategies that overcome some of the weaknesses of the tools developed so far. We have particularly focused on the photocontrol of ionotropic glutamate receptors (iGluRs), which play a key role in the modulation of neuronal excitability. The novel photopharmacological tools developed along this thesis consist in: (i) a PTL based on push-pull-substituted azobenzene photoswitches that responds to two-photon excitation with NIR light.
(ii) a non-destructive caged ligand that enable irreversible and quantitative conversion from the inactive to the active state, thus performing in a similar fashion as CLs but without by-product generation.
(iii) a PCL based on C2-bridged azobenzenes which displays a thermodynamically stable inactive form that selectively turns into the biologically-active state when irradiated.
This thesis reports the synthesis, photochemical characterisation and biological activity evaluation of these three novel photopharmacological approaches.
REFERENCES: [1] R. H. Kramer, A. Mourot, H. Adesnik, Nat. Neurosci. 2013, 16, 816-823.
[2] W. A. Velema, W. Szymanski, B. L. Feringa, J. Am. Chem. Soc. 2014, 136, 2178-2191.
