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

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

School of Chemistry

Research output: Contribution to journal › Article › Research › peer-review

5 Citations (Scopus)

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.

Original language	English
Article number	115655
Number of pages	10
Journal	Bioorganic & Medicinal Chemistry
Volume	28
Issue number	18
DOIs	https://doi.org/10.1016/j.bmc.2020.115655
Publication status	Published - 15 Sept 2020

Keywords

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

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10.1016/j.bmc.2020.115655

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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.",

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AU - Marliac, Marie Adeline

AU - Geoffroy, Chloe

AU - Schmit, Matthieu

AU - Bispat, Anjie

AU - Lewis, Richard J.

AU - Tuck, Kellie L.

AU - Duggan, Peter J.

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AB - 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.

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KW - Ca2.2

KW - Ca3.2

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KW - Pain

KW - T-type calcium channel

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

Abstract

Keywords

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