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.