Inhibition of N-type calcium ion channels by tricyclic antidepressants – experimental and theoretical justification for their use for neuropathic pain

Abstract

A number of tricyclic antidepressants (TCAs) are commonly prescribed off-label for the treatment of neuropathic pain. The blockade of neuronal calcium ion channels is often invoked to partially explain the...

Inhibition of N-type calcium channels by phenoxyaniline and sulfonamide analogues

“…The activity of all analogues for the Ca V 2.2 and Ca V 3.2 channels was evaluated using the previously reported FLIPR calcium imaging assay. 22,23 Ca V 2.2 inhibition was evaluated with the neuroblastoma SH-SY5Y cell line, in the presence of the Ca V 1 blocker nifedipine, and HEK 293T cells expressing recombinant human Ca V 3.2 α 1 subunit were used to evaluate Ca V 3.2 inhibition. The positive control for the Ca V 2.2 channel and Ca V 3.2 channel assay was NNC 55-0396.…”

“…22 The acylated phenoxazine 8 was observed to rapidly hydrolyse in rat plasma (t ½ = 13.9 min) to the corresponding carboxylic acid and phenoxazine, the dihydrodibenzoazepine 9 and dibenzoazepine 10 analogues were more stable, with both having a half-life greater than 60 h. 22 Noting the structural similarity of these latter compounds to tricyclic antidepressants (TCAs), we recently reported Ca V 2.2 inhibition results that support the off-label use of TCAs with neuropathic pain. 23 The research findings highlighted above provided valuable insights for further optimisation of compounds to give improved activity at the Ca V 2.2 and Ca V 3.2 channels, superior pharmacokinetic profiles when compared to MONIRO-1 6a, and more favourable drug-like properties. To overcome the stability challenges observed in several of the phenoxyanilides analogues, two libraries of compounds, replacing the labile amide bond with either a secondary aniline or an isosteric sulfonamide functional group, were prepared.…”

“…6,8 Consequently, several research groups, including our own, have engaged in research programs to develop alternative small molecule Ca V 2.2 (N-type) calcium ion channel blockers for the treatment of neuropathic pain. 9–27 Likewise, various research studies have shown that the Ca V 3.2 (T-type) voltage-gated calcium channel is also a promising therapeutic target for alleviating neuropathic pain. 24–26,28–33…”

“… 22 The acylated phenoxazine 8 was observed to rapidly hydrolyse in rat plasma ( t ½ = 13.9 min) to the corresponding carboxylic acid and phenoxazine, the dihydrodibenzoazepine 9 and dibenzoazepine 10 analogues were more stable, with both having a half-life greater than 60 h. 22 Noting the structural similarity of these latter compounds to tricyclic antidepressants (TCAs), we recently reported Ca V 2.2 inhibition results that support the off-label use of TCAs with neuropathic pain. 23 …”

“…6,8 Consequently, several research groups, including our own, have engaged in research programs to develop alternative small molecule Ca V 2.2 (Ntype) calcium ion channel blockers for the treatment of neuropathic pain. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27] Likewise, various research studies have shown that the Ca V 3.2 (T-type) voltage-gated calcium channel is also a promising therapeutic target for alleviating neuropathic pain. [24][25][26][28][29][30][31][32][33] Over the years, a small number of N-and T-type calcium channel blockers were evaluated in clinical trials for the treatment of neuropathic pain arising from various diseases.…”