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

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. 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.