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.

Rational Design of Photochromic Analogues of Tricyclic Drugs / F. Riefolo, R. Sortino, C. Matera, E. Claro, B. Preda, S. Vitiello, S. Traserra, M. Jiménez, P. Gorostiza. - In: JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0022-2623. - 64:13(2021 Jun 23), pp. 9259-9270. [10.1021/acs.jmedchem.1c00504]

Rational Design of Photochromic Analogues of Tricyclic Drugs

F. Riefolo;C. Matera;
2021-06-23

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.
Settore CHIM/08 - Chimica Farmaceutica
Settore BIO/14 - Farmacologia
Article (author)
File in questo prodotto:
File Dimensione Formato  
Manuscript for 2nd re-submission J Med Chem.pdf

accesso aperto

Tipologia: Pre-print (manoscritto inviato all'editore)
Dimensione 1.78 MB
Formato Adobe PDF
1.78 MB Adobe PDF Visualizza/Apri
acs.jmedchem.1c00504.pdf

accesso riservato

Tipologia: Publisher's version/PDF
Dimensione 2.69 MB
Formato Adobe PDF
2.69 MB Adobe PDF   Visualizza/Apri   Richiedi una copia
Pubblicazioni consigliate

Caricamento pubblicazioni consigliate

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/855420
Citazioni
  • ???jsp.display-item.citation.pmc??? 1
  • Scopus 2
  • ???jsp.display-item.citation.isi??? 3
social impact