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Staff member

Rosalba Sortino
Staff member publications

Matera, Carlo, Calvé, Pablo, Casadó-Anguera, Verònica, Sortino, Rosalba, Gomila, Alexandre MJ., Moreno, Estefanía, Gener, Thomas, Delgado-Sallent, Cristina, Nebot, Pau, Costazza, Davide, Conde-Berriozabal, Sara, Masana, Mercè, Hernando, Jordi, Casadó, Vicent, Puig, MVictoria, Gorostiza, Pau, (2022). Reversible Photocontrol of Dopaminergic Transmission in Wild-Type Animals International Journal Of Molecular Sciences 23, 10114

Understanding the dopaminergic system is a priority in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, and dysregulation of dopaminergic transmission is associated with major neurological disorders. However, the available tools to dissect the endogenous dopaminergic circuits have limited specificity, reversibility, resolution, or require genetic manipulation. Here, we introduce azodopa, a novel photoswitchable ligand that enables reversible spatiotemporal control of dopaminergic transmission. We demonstrate that azodopa activates D1-like receptors in vitro in a light-dependent manner. Moreover, it enables reversibly photocontrolling zebrafish motility on a timescale of seconds and allows separating the retinal component of dopaminergic neurotransmission. Azodopa increases the overall neural activity in the cortex of anesthetized mice and displays illumination-dependent activity in individual cells. Azodopa is the first photoswitchable dopamine agonist with demonstrated efficacy in wild-type animals and opens the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes.

JTD Keywords: behavior, brainwave, d-1, dopamine, gpcr, in vivo electrophysiology, inhibitors, optogenetics, optopharmacology, photochromism, photopharmacology, photoswitch, stimulation, zebrafish, Azobenzene, Receptors


Riefolo, F, Sortino, R, Matera, C, Claro, E, Preda, B, Vitiello, S, Traserra, S, Jimenez, M, Gorostiza, P, (2021). Rational Design of Photochromic Analogues of Tricyclic Drugs Journal Of Medicinal Chemistry 64, 9259-9270

Tricyclic chemical structures are the core of many important drugs targeting all neurotransmitter pathways. These medicines enable effective therapies to treat from peptic ulcer disease to psychiatric disorders. However, when administered systemically, they cause serious adverse effects that limit their use. To obtain localized and on-demand pharmacological action using light, we have designed photoisomerizable ligands based on azobenzene that mimic the tricyclic chemical structure and display reversibly controlled activity. Pseudo-analogues of the tricyclic antagonist pirenzepine demonstrate that this is an effective strategy in muscarinic acetylcholine receptors, showing stronger inhibition upon illumination both in vitro and in cardiac atria ex vivo. Despite the applied chemical modifications to make pirenzepine derivatives sensitive to light stimuli, the most potent candidate of the set, cryptozepine-2, maintained a moderate but promising M-1 vs M-2 subtype selectivity. These photoswitchable crypto-azologs of tricyclic drugs might open a general way to spatiotemporally target their therapeutic action while reducing their systemic toxicity and adverse effects.

JTD Keywords: Binding, M1, Pirenzepine, Rat-brain, Receptor


Riefolo, F., Matera, C., Garrido-Charles, A., Gomila, A., Sortino, R., Agnetta, L., Claro, E., Masgrau, R., Holzgrabe, U., Batlle, M., Decker, M., Guasch, E., Gorostiza, P., (2019). Optical control of cardiac function with a photoswitchable muscarinic agonist Journal of the American Chemical Society 141, (18), 7628-7636

Light-triggered reversible modulation of physiological functions offers the promise of enabling on-demand spatiotemporally controlled therapeutic interventions. Optogenetics has been successfully implemented in the heart, but significant barriers to its use in the clinic remain, such as the need for genetic transfection. Herein, we present a method to modulate cardiac function with light through a photoswitchable compound and without genetic manipulation. The molecule, named PAI, was designed by introduction of a photoswitch into the molecular structure of an M2 mAChR agonist. In vitro assays revealed that PAI enables light-dependent activation of M2 mAChRs. To validate the method, we show that PAI photoisomers display different cardiac effects in a mammalian animal model, and demonstrate reversible, real-time photocontrol of cardiac function in translucent wildtype tadpoles. PAI can also effectively activate M2 receptors using two-photon excitation with near-infrared light, which overcomes the scattering and low penetration of short-wave-length illumination, and offers new opportunities for intravital imaging and control of cardiac function.

JTD