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

doi:10.1016/j.bmc.2020.115655

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. Epub 2020 Jul 20.

Authors

Fernanda C Cardoso¹, Marie-Adeline Marliac², Chloe Geoffroy², Matthieu Schmit³, Anjie Bispat³, Richard J Lewis¹, Kellie L Tuck⁴, Peter J Duggan⁵

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: kellie.tuck@monash.edu.
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: peter.duggan@csiro.au.

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 Ca_V2.2 channel in the SH-SY5Y neuroblastoma cell line. These analogues also showed promising activity towards the Ca_V3.2 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anilides / chemical synthesis*
Anilides / metabolism
Animals
Antineoplastic Agents / chemical synthesis*
Antineoplastic Agents / metabolism
Antineoplastic Agents / pharmacology
Benzodiazepines / chemistry*
Blood-Brain Barrier / metabolism
Calcium / metabolism
Calcium Channel Blockers / chemical synthesis*
Calcium Channel Blockers / metabolism
Calcium Channel Blockers / pharmacology
Calcium Channels / genetics
Calcium Channels / metabolism*
Cell Line, Tumor
Drug Screening Assays, Antitumor
Humans
Models, Molecular
Neuralgia / drug therapy*
Neurons / metabolism
Rats, Sprague-Dawley
Recombinant Proteins / genetics
Recombinant Proteins / metabolism*
Signal Transduction
Structure-Activity Relationship

Substances

Anilides
Antineoplastic Agents
Calcium Channel Blockers
Calcium Channels
MONIRO-1
Recombinant Proteins
Benzodiazepines
Calcium