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

Authors

Jeffrey R. McArthur, University of Wollongong, RMIT UniversityFollow
Leonid Motin, University of Wollongong, RMIT University
Ellen Gleeson, CSIRO Manufacturing, Monash University
Sandro Spiller, Monash University
Richard J. Lewis, University of Queensland
Peter J. Duggan, University of QueenslandFollow
Kellie L. Tuck, Monash University
David J. Adams, University of Wollongong, RMIT UniversityFollow

RIS ID

128230

Publication Details

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.

Abstract

Background and Purpose: Voltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Ca_v2.2) and T-type (Ca_v3.1, Ca_v3.2 and Ca_v3.3) 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_v1.2, Ca_v1.3, Ca_v2.1, Ca_v2.2, Ca_v2.3, Ca_v3.1, Ca_v3.2 and Ca_v3.3. Key Results: MONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCa_v3.1, hCa_v3.2 and hCa_v3.3 (IC₅₀ : 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCa_v2.2 (IC₅₀ : 34.0 ± 3.6 μM). It interacted with L-type calcium channels Ca_v1.2 and Ca_v1.3 with significantly lower potency (IC₅₀ > 100 μM) and did not inhibit hCa_v2.1 or hCa_v2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCa_v2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCa_v3.1 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_v2.2 and hCa_v3.1 channels. Such Ca_v channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies.

Grant Number

NHMRC/1072113