• Jeffrey R McArthur, Leonid Motin, Ellen C Gleeson, Sandro Spiller, Richard J Lewis, Peter J Duggan, Kellie L Tuck, and David J Adams.
• Illawarra Health and Medical Research Institute, University of Wollongong, Wollongong, NSW, Australia.
• Br. J. Pharmacol. 2018 Jun 1; 175 (12): 2284-2295.

Background And PurposeVoltage-gated calcium channels are involved in nociception in the CNS and in the periphery. N-type (Cav 2.2) and T-type (Cav 3.1, Cav 3.2 and Cav 3.3) voltage-gated calcium channels are particularly important in studying and treating pain and epilepsy.Experimental ApproachIn 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 Cav 1.2, Cav 1.3, Cav 2.1, Cav 2.2, Cav 2.3, Cav 3.1, Cav 3.2 and Cav 3.3.Key ResultsMONIRO-1 was 5- to 20-fold more potent at inhibiting human T-type calcium channels, hCav 3.1, hCav 3.2 and hCav 3.3 (IC50 : 3.3 ± 0.3, 1.7 ± 0.1 and 7.2 ± 0.3 μM, respectively) than N-type calcium channel, hCav 2.2 (IC50 : 34.0 ± 3.6 μM). It interacted with L-type calcium channels Cav 1.2 and Cav 1.3 with significantly lower potency (IC50  > 100 μM) and did not inhibit hCav 2.1 or hCav 2.3 channels at concentrations as high as 100 μM. State- and use-dependent inhibition of hCav 2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCav 3.1 channels suggesting a different mode of action between these two channels.Conclusions And ImplicationsSelectivity, 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 hCav 2.2 and hCav 3.1 channels. Such Cav channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies.Linked ArticlesThis 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.© 2017 The British Pharmacological Society.

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