{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,12]],"date-time":"2026-05-12T20:09:07Z","timestamp":1778616547991,"version":"3.51.4"},"reference-count":66,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2017,7,21]],"date-time":"2017-07-21T00:00:00Z","timestamp":1500595200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"NHMRC Program Grant","award":["APP1072113"],"award-info":[{"award-number":["APP1072113"]}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2018,6]]},"abstract":"<jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Voltage\u2010gated calcium channels are involved in nociception in the CNS and in the periphery. N\u2010type (Ca<jats:sub>v<\/jats:sub>2.2) and T\u2010type (Ca<jats:sub>v<\/jats:sub>3.1, Ca<jats:sub>v<\/jats:sub>3.2 and Ca<jats:sub>v<\/jats:sub>3.3) voltage\u2010gated calcium channels are particularly important in studying and treating pain and epilepsy.<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>In this study, whole\u2010cell patch clamp electrophysiology was used to assess the potency and mechanism of action of a novel<jats:italic>ortho<\/jats:italic>\u2010phenoxylanilide derivative, MONIRO\u20101, against a panel of voltage\u2010gated calcium channels including Ca<jats:sub>v<\/jats:sub>1.2, Ca<jats:sub>v<\/jats:sub>1.3, Ca<jats:sub>v<\/jats:sub>2.1, Ca<jats:sub>v<\/jats:sub>2.2, Ca<jats:sub>v<\/jats:sub>2.3, Ca<jats:sub>v<\/jats:sub>3.1, Ca<jats:sub>v<\/jats:sub>3.2 and Ca<jats:sub>v<\/jats:sub>3.3.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>MONIRO\u20101 was 5\u2010 to 20\u2010fold more potent at inhibiting human T\u2010type calcium channels, hCa<jats:sub>v<\/jats:sub>3.1, hCa<jats:sub>v<\/jats:sub>3.2 and hCa<jats:sub>v<\/jats:sub>3.3 (IC<jats:sub>50<\/jats:sub>: 3.3\u00a0\u00b1\u00a00.3, 1.7\u00a0\u00b1\u00a00.1 and 7.2\u00a0\u00b1\u00a00.3\u00a0\u03bcM, respectively) than N\u2010type calcium channel, hCa<jats:sub>v<\/jats:sub>2.2 (IC<jats:sub>50<\/jats:sub>: 34.0\u00a0\u00b1\u00a03.6\u00a0\u03bcM). It interacted with L\u2010type calcium channels Ca<jats:sub>v<\/jats:sub>1.2 and Ca<jats:sub>v<\/jats:sub>1.3 with significantly lower potency (IC<jats:sub>50<\/jats:sub>\u00a0&gt;\u00a0100\u00a0\u03bcM) and did not inhibit hCa<jats:sub>v<\/jats:sub>2.1 or hCa<jats:sub>v<\/jats:sub>2.3 channels at concentrations as high as 100\u00a0\u03bcM. State\u2010 and use\u2010dependent inhibition of hCa<jats:sub>v<\/jats:sub>2.2 channels was observed, whereas stronger inhibition occurred at high stimulation frequencies for hCa<jats:sub>v<\/jats:sub>3.1 channels suggesting a different mode of action between these two channels.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions and Implications<\/jats:title><jats:p>Selectivity, potency, reversibility and multi\u2010modal effects distinguish MONIRO\u20101 from other low MW inhibitors acting on Ca<jats:sub>v<\/jats:sub>channels involved in pain and\/or epilepsy pathways. High\u2010frequency firing increased the affinity for MONIRO\u20101 for both hCa<jats:sub>v<\/jats:sub>2.2 and hCa<jats:sub>v<\/jats:sub>3.1 channels. Such Ca<jats:sub>v<\/jats:sub>channel modulators have potential clinical use in the treatment of epilepsies, neuropathic pain and other nociceptive pathophysiologies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Linked Articles<\/jats:title><jats:p>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<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v175.12\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v175.12\/issuetoc<\/jats:ext-link><\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.13910","type":"journal-article","created":{"date-parts":[[2017,6,13]],"date-time":"2017-06-13T12:00:38Z","timestamp":1497355238000},"page":"2284-2295","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Inhibition of human N\u2010 and T\u2010type calcium channels by an<i>ortho<\/i>\u2010phenoxyanilide derivative, MONIRO\u20101"],"prefix":"10.1111","volume":"175","author":[{"given":"Jeffrey R","family":"McArthur","sequence":"first","affiliation":[{"name":"Illawarra Health and Medical Research Institute University of Wollongong Wollongong NSW Australia"},{"name":"Health Innovations Research 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