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Papers of the Week

2020 Sep 15

Bioorg Med Chem



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


Cardoso FC, Marliac M-A, Geoffroy C, Schmit M, Bispat A, Lewis RJ, Tuck KL, Duggan PJ
Bioorg Med Chem. 2020 Sep 15; 28(18):115655.
PMID: 32828422.


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 Ca2.2 channel in the SH-SY5Y neuroblastoma cell line. These analogues also showed promising activity towards the Ca3.2 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.