Panx-1 is a membrane channel protein involved in some pathologies such as ischemic stroke, cancer and neuropathic pain, thus representing a promising therapeutic target. We present here a study aimed at obtaining the first class of selective Panx-1 blockers, a new topic for pharmaceutical chemistry, since all compounds used so far for the study of this channel have different primary targets. Among various scaffolds analyzed, the indole nucleous emerged, whose elaboration yielded interesting Panx-1 blockers, such as the potent 5-sulfamoyl derivatives 14c and 15b (I%= 100 at 50 µM). In vivo tests performed in the mouse model of oxaliplatin-induced neuropathy, demonstrated that the hypersensitivity was completely reverted by treatment with 15b (1 nmol, administered intrathecally), suggesting a relationship between this effect and the channel blocking ability. Finally, we decided to perform a virtual screening study on compounds 5b, 6l and 14c using a recently resolved cryo-EM structure of hPanx-1 channel, to try to relate the potency of our new inhibitors.

Design and synthesis of the first indole-based blockers of Panx-1 channel / Crocetti, Letizia; Guerrini, Gabriella; Puglioli, Sara; Giovannoni, Maria Paola; Di Cesare Mannelli, Lorenzo; Lucarini, Elena; Ghelardini, Carla; Wang, Junjie; Dahl, Gerhard. - In: EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY. - ISSN 0223-5234. - ELETTRONICO. - 223:(2021), pp. 113650-113660. [10.1016/j.ejmech.2021.113650]

Design and synthesis of the first indole-based blockers of Panx-1 channel

Crocetti, Letizia;Guerrini, Gabriella;Giovannoni, Maria Paola
;
Di Cesare Mannelli, Lorenzo;Lucarini, Elena;Ghelardini, Carla;
2021

Abstract

Panx-1 is a membrane channel protein involved in some pathologies such as ischemic stroke, cancer and neuropathic pain, thus representing a promising therapeutic target. We present here a study aimed at obtaining the first class of selective Panx-1 blockers, a new topic for pharmaceutical chemistry, since all compounds used so far for the study of this channel have different primary targets. Among various scaffolds analyzed, the indole nucleous emerged, whose elaboration yielded interesting Panx-1 blockers, such as the potent 5-sulfamoyl derivatives 14c and 15b (I%= 100 at 50 µM). In vivo tests performed in the mouse model of oxaliplatin-induced neuropathy, demonstrated that the hypersensitivity was completely reverted by treatment with 15b (1 nmol, administered intrathecally), suggesting a relationship between this effect and the channel blocking ability. Finally, we decided to perform a virtual screening study on compounds 5b, 6l and 14c using a recently resolved cryo-EM structure of hPanx-1 channel, to try to relate the potency of our new inhibitors.
2021
223
113650
113660
Goal 3: Good health and well-being for people
Crocetti, Letizia; Guerrini, Gabriella; Puglioli, Sara; Giovannoni, Maria Paola; Di Cesare Mannelli, Lorenzo; Lucarini, Elena; Ghelardini, Carla; Wang...espandi
File in questo prodotto:
File Dimensione Formato  
EJMECH-S-21-00203.pdf

Accesso chiuso

Tipologia: Altro
Licenza: Tutti i diritti riservati
Dimensione 3.84 MB
Formato Adobe PDF
3.84 MB Adobe PDF   Richiedi una copia

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

Utilizza questo identificatore per citare o creare un link a questa risorsa: https://hdl.handle.net/2158/1238611
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 9
  • ???jsp.display-item.citation.isi??? 8
social impact