{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T10:13:55Z","timestamp":1760782435572},"reference-count":34,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2009,2,2]],"date-time":"2009-02-02T00:00:00Z","timestamp":1233532800000},"content-version":"vor","delay-in-days":2346,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2002,9]]},"abstract":"<jats:p>\n<jats:list list-type=\"explicit-label\">\n<jats:list-item>\n<jats:p>The structural features that determine the state\u2010dependent interaction of local anaesthetics with voltage\u2010operated sodium channels are still a matter of debate. We have studied the blockade of sodium channels by 2,6\u2010dimethylphenol, a phenol derivative which resembles the aromatic tail of lidocaine, etidocaine, and bupivacaine.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>The effects of 2,6\u2010dimethylphenol were studied on heterologously (HEK 293) expressed rat neuronal (rat brain IIA) and human skeletal muscle (hSkM1) sodium channels using whole\u2010cell voltage\u2010clamp experiments.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>2,6\u2010Dimethylphenol was effective in blocking whole\u2010cell sodium inward currents. Its potency was comparable to the potency of lidocaine previously obtained with similar protocols by others. The IC<jats:sub>50<\/jats:sub> at \u221270 mV holding potential was 150 and 187 \u03bc<jats:sc>M<\/jats:sc> for the skeletal muscle and the neuronal isoform, respectively. In both isoforms, the blocking potency increased with the fraction of inactivated channels at depolarized holding potentials. However, the block achieved at \u221270 mV with respect to \u2212150 mV holding potential was significantly higher only in the skeletal muscle isoform. The estimated dissociation constant K<jats:sub>d<\/jats:sub> from the inactivated state was 25 \u03bc<jats:sc>M<\/jats:sc> and 28 \u03bc<jats:sc>M<\/jats:sc> in the skeletal muscle and the neuronal isoform, respectively. The kinetics of drug equilibration between resting and inactivated channel states were about 10 fold faster compared with lidocaine.<\/jats:p>\n<\/jats:list-item>\n<jats:list-item>\n<jats:p>Our results show that the blockade induced by 2,6\u2010dimethylphenol retains voltage\u2010dependency, a typical feature of lidocaine\u2010like local anaesthetics. This is consistent with the hypothesis that the \u2018aromatic tail\u2019 determines the state\u2010dependent interaction of local anaesthetics with the sodium channel.<\/jats:p>\n<\/jats:list-item>\n<\/jats:list>\n<\/jats:p><jats:p><jats:italic>British Journal of Pharmacology<\/jats:italic> (2002) <jats:bold>137<\/jats:bold>, 285\u2013293. doi:<jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"doi\" xlink:href=\"10.1038\/sj.bjp.0704854\">10.1038\/sj.bjp.0704854<\/jats:ext-link><\/jats:p>","DOI":"10.1038\/sj.bjp.0704854","type":"journal-article","created":{"date-parts":[[2002,9,3]],"date-time":"2002-09-03T16:43:08Z","timestamp":1031071388000},"page":"285-293","update-policy":"http:\/\/dx.doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Block of voltage\u2010operated sodium channels by 2,6\u2010dimethylphenol, a structural analogue of lidocaine's aromatic tail"],"prefix":"10.1111","volume":"137","author":[{"given":"Gertrud","family":"Haeseler","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johannes","family":"Bufler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Merken","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Reinhard","family":"Dengler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeffrey","family":"Aronson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin","family":"Leuwer","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2009,2,2]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1172\/JCI119116"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.107.5.643"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.1085\/jgp.81.5.613"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1989.tb08534.x"},{"key":"e_1_2_7_6_1","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1152\/physrev.1992.72.suppl_4.S15","article-title":"Cellular and molecular biology of voltage\u2010gated sodium channels","volume":"72","author":"CATTERALL W.A.","year":"1992","journal-title":"Physiol. 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