The neuronal calcium ion channel activity of constrained analogues of MONIRO-1

Fernanda C. Cardoso, Marie-Adeline Marliac, Chloe Geoffroy, Matthieu Schmit, Anjie Bispat, Richard J. Lewis, Kellie L. Tuck, Peter J. Duggan

Research output: Contribution to journalArticlepeer-review

Abstract

Structural modifications of the neuronal calcium channel blocker MONIRO-1, including constraining the phenoxyaniline portion of the molecule and replacing the guanidinium functionality with tertiary amines, led to compounds with significantly improved affinities for the endogenously expressed CaV2.2 channel in the SH-SY5Y neuroblastoma cell line. These analogues also showed promising activity towards the CaV3.2 channel, recombinantly expressed in HEK293T cells. Both of these ion channels have received attention as likely targets for the treatment of neuropathic pain. The dibenzoazepine and dihydrobenzodiazepine derivatives prepared in this study show an encouraging combination of neuronal calcium ion channel inhibitory potency, plasma stability and potential to cross the blood–brain-barrier.

Original languageEnglish
Article number115655
Number of pages10
JournalBioorganic and Medicinal Chemistry
Volume28
Issue number18
DOIs
Publication statusPublished - 15 Sep 2020

Keywords

  • Benzodiazepine
  • Ca2.2
  • Ca3.2
  • N-type calcium channel
  • Pain
  • T-type calcium channel

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