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

Letizia Crocetti, Gabriella Guerrini, Sara Puglioli, Maria Paola Giovannoni, Lorenzo Di Cesare Mannelli, Elena Lucarini, Carla Ghelardini, Junjie Wang, Gerhard Dahl

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Article number113650
JournalEuropean Journal of Medicinal Chemistry
Volume223
DOIs
StatePublished - Nov 5 2021

Keywords

  • Channel blockers
  • Indole scaffold
  • Molecular modeling
  • Neuropathic pain
  • Panx-1

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

Fingerprint

Dive into the research topics of 'Design and synthesis of the first indole-based blockers of Panx-1 channel'. Together they form a unique fingerprint.

Cite this