Skip to main content
placeholder image

Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1

Journal Article


Download full-text (Open Access)

Abstract


  • Background and Purpose: Voltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Ca v 2.2) and T-type (Ca v 3.1, Ca v 3.2 and Ca v 3.3) voltage-gated calcium channels are particularly important in studying and treating pain and epilepsy.

    Experimental Approach: In this study, whole-cell patch clamp electrophysiology was used to assess the potency and mechanism of action of a novel ortho-phenoxylanilide derivative, MONIRO-1, against a panel of voltage-gated calcium channels including Ca v 1.2, Ca v 1.3, Ca v 2.1, Ca v 2.2, Ca v 2.3, Ca v 3.1, Ca v 3.2 and Ca v 3.3.

    Key Results: MONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCa v 3.1, hCa v 3.2 and hCa v 3.3 (IC 50 : 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCa v 2.2 (IC 50 : 34.0 ± 3.6 μM). It interacted with L-type calcium channels Ca v 1.2 and Ca v 1.3 with significantly lower potency (IC 50   >  100 μM) and did not inhibit hCa v 2.1 or hCa v 2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCa v 2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCa v 3.1 channels suggesting a different mode of action between these two channels.

    Conclusions and Implications: Selectivity, potency, reversibility and multi-modal effects distinguish MONIRO-1 from other low MW inhibitors acting on Ca v channels involved in pain and/or epilepsy pathways. High-frequency firing increased the affinity for MONIRO-1 for both hCa v 2.2 and hCa v 3.1 channels. Such Ca v channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies.

UOW Authors


  •   McArthur, Jeff R.
  •   Motin, Leonid (external author)
  •   Gleeson, Ellen (external author)
  •   Spiller, Sandro (external author)
  •   Lewis, Richard J. (external author)
  •   Duggan, Peter J. (external author)
  •   Tuck, Kellie L. (external author)
  •   Adams, David

Publication Date


  • 2018

Citation


  • McArthur, J. R., Motin, L., Gleeson, E. C., Spiller, S., Lewis, R. J., Duggan, P. J., Tuck, K. L. & Adams, D. J. (2018). Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1. British Journal of Pharmacology, 175 (12), 2284-2295.

Scopus Eid


  • 2-s2.0-85047951872

Ro Full-text Url


  • https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2289&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1262

Number Of Pages


  • 11

Start Page


  • 2284

End Page


  • 2295

Volume


  • 175

Issue


  • 12

Place Of Publication


  • United Kingdom

Abstract


  • Background and Purpose: Voltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Ca v 2.2) and T-type (Ca v 3.1, Ca v 3.2 and Ca v 3.3) voltage-gated calcium channels are particularly important in studying and treating pain and epilepsy.

    Experimental Approach: In this study, whole-cell patch clamp electrophysiology was used to assess the potency and mechanism of action of a novel ortho-phenoxylanilide derivative, MONIRO-1, against a panel of voltage-gated calcium channels including Ca v 1.2, Ca v 1.3, Ca v 2.1, Ca v 2.2, Ca v 2.3, Ca v 3.1, Ca v 3.2 and Ca v 3.3.

    Key Results: MONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCa v 3.1, hCa v 3.2 and hCa v 3.3 (IC 50 : 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCa v 2.2 (IC 50 : 34.0 ± 3.6 μM). It interacted with L-type calcium channels Ca v 1.2 and Ca v 1.3 with significantly lower potency (IC 50   >  100 μM) and did not inhibit hCa v 2.1 or hCa v 2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCa v 2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCa v 3.1 channels suggesting a different mode of action between these two channels.

    Conclusions and Implications: Selectivity, potency, reversibility and multi-modal effects distinguish MONIRO-1 from other low MW inhibitors acting on Ca v channels involved in pain and/or epilepsy pathways. High-frequency firing increased the affinity for MONIRO-1 for both hCa v 2.2 and hCa v 3.1 channels. Such Ca v channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies.

UOW Authors


  •   McArthur, Jeff R.
  •   Motin, Leonid (external author)
  •   Gleeson, Ellen (external author)
  •   Spiller, Sandro (external author)
  •   Lewis, Richard J. (external author)
  •   Duggan, Peter J. (external author)
  •   Tuck, Kellie L. (external author)
  •   Adams, David

Publication Date


  • 2018

Citation


  • McArthur, J. R., Motin, L., Gleeson, E. C., Spiller, S., Lewis, R. J., Duggan, P. J., Tuck, K. L. & Adams, D. J. (2018). Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1. British Journal of Pharmacology, 175 (12), 2284-2295.

Scopus Eid


  • 2-s2.0-85047951872

Ro Full-text Url


  • https://ro.uow.edu.au/cgi/viewcontent.cgi?article=2289&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/1262

Number Of Pages


  • 11

Start Page


  • 2284

End Page


  • 2295

Volume


  • 175

Issue


  • 12

Place Of Publication


  • United Kingdom