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Title: Rational Design of Photochromic Analogues of Tricyclic Drugs
Author: Riefolo, Fabio
Sortino, Rosalba
Matera, Carlo
Claro Izaguirre, Enrique
Preda, Beatrice
Vitiello, Simone
Traserra, Sara
Jiménez, Marcel
Gorostiza Langa, Pablo Ignacio
Keywords: Medicaments
Issue Date: 23-Jun-2021
Publisher: ACS Publications
Abstract: 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 M1 vs M2 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.
Note: Versió postprint del document publicat a:
It is part of: Journal of Medicinal Chemistry, 2021, vol. 64, num.13, p. 9259-9270
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ISSN: 0022-2623
Appears in Collections:Articles publicats en revistes (Institut de Bioenginyeria de Catalunya (IBEC))

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