posted on 2024-11-16, 03:14authored byJeffrey McArthur, Leonid Motin, Ellen Gleeson, Sandro Spiller, Richard J Lewis, Peter J Duggan, Kellie L Tuck, David AdamsDavid Adams
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 Ca v 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.
Funding
Discovery and development of better pain treatments
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.