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

McArthur, J, Motin, L, Gleeson, E, Spiller, S, Lewis, R, Duggan, P, Tuck, K and Adams, D 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.

Document type: Journal Article
Collection: Journal Articles

Title Inhibition of human N- and T-type calcium channels by an ortho-phenoxyanilide derivative, MONIRO-1
Author(s) McArthur, J
Motin, L
Gleeson, E
Spiller, S
Lewis, R
Duggan, P
Tuck, K
Adams, D
Year 2018
Journal name British Journal of Pharmacology
Volume number 175
Issue number 12
Start page 2284
End page 2295
Total pages 12
Publisher John Wiley and Sons
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 ?M, respectively) than N-type calcium channel, hCav2.2 (IC50: 34.0 ± 3.6 ?M). It interacted with L-type calcium channels Cav1.2 and Cav1.3 with significantly lower potency (IC50 > 100 ?M) and did not inhibit hCav2.1 or hCav2.3 channels at concentrations as high as 100 ?M. 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
Subject Pharmacology and Pharmaceutical Sciences not elsewhere classified
DOI - identifier 10.1111/bph.13910
Copyright notice © 2017 The British Pharmacological Society
ISSN 0007-1188
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