2. Academic Validation
  3. The neuronal calcium ion channel activity of constrained analogues of MONIRO-1

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

  • Bioorg Med Chem. 2020 Sep 15;28(18):115655. doi: 10.1016/j.bmc.2020.115655.
Fernanda C Cardoso 1,  Marie-Adeline Marliac 2,  Chloe Geoffroy 2,  Matthieu Schmit 3,  Anjie Bispat 3,  Richard J Lewis 1,  Kellie L Tuck 4,  Peter J Duggan 5
Affiliations

Affiliations

  • 1 Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
  • 2 CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia; Institut de Recherche de Chimie Paris, CNRS - Chimie Paris Tech, 11 rue Pierre et Marie Curie, Paris 75005, France.
  • 3 CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia; School of Chemistry, Monash University, Victoria 3800, Australia.
  • 4 School of Chemistry, Monash University, Victoria 3800, Australia. Electronic address: [email protected].
  • 5 CSIRO Manufacturing, Bag 10, Clayton South, Victoria 3169, Australia; College of Science and Engineering, Flinders University, GPO Box 2100, Adelaide, South Australia, Australia. Electronic address: [email protected].
PMID: 32828422 DOI: 10.1016/j.bmc.2020.115655
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.

Keywords

Benzodiazepine; Ca(V)2.2; Ca(V)3.2; N-type calcium channel; Pain; T-type calcium channel.

Figures
Products