In:
British Journal of Pharmacology, Wiley, Vol. 175, No. 12 ( 2018-06), p. 2284-2295
Abstract:
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
Type of Medium:
Online Resource
ISSN:
0007-1188
,
1476-5381
Language:
English
Publisher:
Wiley
Publication Date:
2018
detail.hit.zdb_id:
2029728-2
SSG:
15,3
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