Light-mediated Activation/Deactivation Control and in vitro ADMETox Profiling of a Donepezil-like Dual AChE/MAO-B Inhibitor.

IF 4.3 3区 医学 Q1 PHARMACOLOGY & PHARMACY European Journal of Pharmaceutical Sciences Pub Date : 2025-03-08 DOI:10.1016/j.ejps.2025.107066
Federica Poggialini, Paolo Governa, Chiara Vagaggini, Samuele Maramai, Stefania Lamponi, Claudia Mugnaini, Antonella Brizzi, Rosa Purgatorio, Modesto De Candia, Marco Catto, Elena Dreassi, Fabrizio Manetti, Federico Corelli, Cosimo Damiano Altomare, Andrea Cappelli, Marco Paolino
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Abstract

The possibility to control the effects of drugs in time and space represents an ideal condition for developing safer and more personalized therapies against different disorders. In this context, photopharmacology has paved the way for the use of light in the modulation of drugs activity. Our interest is directed to photo-switchable molecules, capable of interconverting between two different isoforms upon light irradiation. We recently reported compound 1, a donepezil-like based on 2-benzylidenindan-1-one structure, as a dual AChE and MAO-B inhibitor, which can be converted into the E- (active form) and Z- (about tenfold less active form) diastereoisomers by irradiating with UV-vis light. Aiming at identifying compounds with remarkable activity in a physiological conditions, we herein report a fine characterization of compound 1 in PBS solutions. First, we evaluated its ability to act as a photoswitch comparing PBS solution with organic solvents (e.g. methanol), demonstrating that a wavelength in the UV range (330 nm) can convert the E- into the Z-diastereoisomer, while the use of a visible light (400 nm) allows the interconversion from Z to E in both media. Along with its photoinducible behavior, we investigated the passive diffusion across cellular membrane with PAMPA experiments, plasma and microsomal stability, and binding to plasma proteins. Interestingly, the results of such studies suggested that compound 1 could persist in the blood circulation for a long time, which is desirable for application in photopharmacological therapies. Cytotoxicity studies highlighted the potential of our prototypic compound as a lead photodrug against neurodegenerative disorders, deserving to advance in molecular optimization studies and further in vitro and in vivo characterization.

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CiteScore
9.60
自引率
2.20%
发文量
248
审稿时长
50 days
期刊介绍: The journal publishes research articles, review articles and scientific commentaries on all aspects of the pharmaceutical sciences with emphasis on conceptual novelty and scientific quality. The Editors welcome articles in this multidisciplinary field, with a focus on topics relevant for drug discovery and development. More specifically, the Journal publishes reports on medicinal chemistry, pharmacology, drug absorption and metabolism, pharmacokinetics and pharmacodynamics, pharmaceutical and biomedical analysis, drug delivery (including gene delivery), drug targeting, pharmaceutical technology, pharmaceutical biotechnology and clinical drug evaluation. The journal will typically not give priority to manuscripts focusing primarily on organic synthesis, natural products, adaptation of analytical approaches, or discussions pertaining to drug policy making. Scientific commentaries and review articles are generally by invitation only or by consent of the Editors. Proceedings of scientific meetings may be published as special issues or supplements to the Journal.
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