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

Jeffrey R McArthur, Leonid Motin, Ellen C Gleeson, Sandro Spiller, Richard J Lewis, Peter J. Duggan, Kellie L Tuck, David J Adams

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Background and Purpose: Voltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Cav2.2) and T-type (Cav3.1, Cav3.2 and Cav3.3) 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 Cav1.2, Cav1.3, Cav2.1, Cav2.2, Cav2.3, Cav3.1, Cav3.2 and Cav3.3. Key Results: MONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCav3.1, hCav3.2 and hCav3.3 (IC50: 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCav2.2 (IC50: 34.0 ± 3.6 μM). It interacted with L-type calcium channels Cav1.2 and Cav1.3 with significantly lower potency (IC50 > 100 μM) and did not inhibit hCav2.1 or hCav2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCav2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCav3.1 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 Cav channels involved in pain and/or epilepsy pathways. High-frequency firing increased the affinity for MONIRO-1 for both hCav2.2 and hCav3.1 channels. Such Cav channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies. Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

Original languageEnglish
Pages (from-to)2284-2295
Number of pages12
JournalBritish Journal of Pharmacology
Volume175
Issue number12
DOIs
Publication statusPublished - 1 Jun 2018

Cite this

McArthur, J. R., Motin, L., Gleeson, E. C., Spiller, S., Lewis, R. J., Duggan, P. J., ... 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. https://doi.org/10.1111/bph.13910
McArthur, Jeffrey R ; Motin, Leonid ; Gleeson, Ellen C ; Spiller, Sandro ; Lewis, Richard J ; Duggan, Peter J. ; Tuck, Kellie L ; Adams, David J. / Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1. In: British Journal of Pharmacology. 2018 ; Vol. 175, No. 12. pp. 2284-2295.
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title = "Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1",
abstract = "Background and Purpose: Voltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Cav2.2) and T-type (Cav3.1, Cav3.2 and Cav3.3) 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 Cav1.2, Cav1.3, Cav2.1, Cav2.2, Cav2.3, Cav3.1, Cav3.2 and Cav3.3. Key Results: MONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCav3.1, hCav3.2 and hCav3.3 (IC50: 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCav2.2 (IC50: 34.0 ± 3.6 μM). It interacted with L-type calcium channels Cav1.2 and Cav1.3 with significantly lower potency (IC50 > 100 μM) and did not inhibit hCav2.1 or hCav2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCav2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCav3.1 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 Cav channels involved in pain and/or epilepsy pathways. High-frequency firing increased the affinity for MONIRO-1 for both hCav2.2 and hCav3.1 channels. Such Cav channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies. Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.",
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McArthur, JR, Motin, L, Gleeson, EC, Spiller, S, Lewis, RJ, Duggan, PJ, Tuck, KL & Adams, DJ 2018, 'Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1', British Journal of Pharmacology, vol. 175, no. 12, pp. 2284-2295. https://doi.org/10.1111/bph.13910

Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1. / McArthur, Jeffrey R; Motin, Leonid; Gleeson, Ellen C; Spiller, Sandro; Lewis, Richard J; Duggan, Peter J.; Tuck, Kellie L; Adams, David J.

In: British Journal of Pharmacology, Vol. 175, No. 12, 01.06.2018, p. 2284-2295.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1

AU - McArthur, Jeffrey R

AU - Motin, Leonid

AU - Gleeson, Ellen C

AU - Spiller, Sandro

AU - Lewis, Richard J

AU - Duggan, Peter J.

AU - Tuck, Kellie L

AU - Adams, David J

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background and Purpose: Voltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Cav2.2) and T-type (Cav3.1, Cav3.2 and Cav3.3) 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 Cav1.2, Cav1.3, Cav2.1, Cav2.2, Cav2.3, Cav3.1, Cav3.2 and Cav3.3. Key Results: MONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCav3.1, hCav3.2 and hCav3.3 (IC50: 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCav2.2 (IC50: 34.0 ± 3.6 μM). It interacted with L-type calcium channels Cav1.2 and Cav1.3 with significantly lower potency (IC50 > 100 μM) and did not inhibit hCav2.1 or hCav2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCav2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCav3.1 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 Cav channels involved in pain and/or epilepsy pathways. High-frequency firing increased the affinity for MONIRO-1 for both hCav2.2 and hCav3.1 channels. Such Cav channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies. Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

AB - Background and Purpose: Voltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Cav2.2) and T-type (Cav3.1, Cav3.2 and Cav3.3) 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 Cav1.2, Cav1.3, Cav2.1, Cav2.2, Cav2.3, Cav3.1, Cav3.2 and Cav3.3. Key Results: MONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCav3.1, hCav3.2 and hCav3.3 (IC50: 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCav2.2 (IC50: 34.0 ± 3.6 μM). It interacted with L-type calcium channels Cav1.2 and Cav1.3 with significantly lower potency (IC50 > 100 μM) and did not inhibit hCav2.1 or hCav2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCav2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCav3.1 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 Cav channels involved in pain and/or epilepsy pathways. High-frequency firing increased the affinity for MONIRO-1 for both hCav2.2 and hCav3.1 channels. Such Cav channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies. Linked Articles: This article is part of a themed section on Recent Advances in Targeting Ion Channels to Treat Chronic Pain. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.12/issuetoc.

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