{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T10:30:31Z","timestamp":1760783431679,"version":"3.38.0"},"reference-count":43,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,1,25]],"date-time":"2012-01-25T00:00:00Z","timestamp":1327449600000},"content-version":"vor","delay-in-days":0,"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":[[2012,2]]},"abstract":"<jats:p><jats:bold>BACKGROUND AND PURPOSE<\/jats:bold>Enhancement of GABAergic function is the primary mechanism of important therapeutic agents such as benzodiazepines, barbiturates, neurosteroids, general anaesthetics and some anticonvulsants. Despite their chemical diversity, many studies have postulated that these agents may bind at a common or overlapping binding site, or share an activation domain. Similarly, we found that flavan\u20103\u2010ol esters act as positive modulators of GABA<jats:sub>A<\/jats:sub>receptors, and noted that this action resembled the<jats:italic>in vitro<\/jats:italic>profile of general anaesthetics. In this study we further investigated the interactions between these agents.<\/jats:p><jats:p><jats:bold>EXPERIMENTAL APPROACH<\/jats:bold>Using two\u2010electrode voltage clamp electrophysiological recordings on receptors of known subunit composition expressed in<jats:italic>Xenopus<\/jats:italic>oocytes, we evaluated positive modulation by etomidate, loreclezole, diazepam, thiopentone, 5\u03b1\u2010pregnan\u20103\u03b1\u2010ol\u201020\u2010one (THP) and the flavan\u20103\u2010ol ester 2S,3R\u2010<jats:italic>trans<\/jats:italic>3\u2010acetoxy\u20104\u2032\u2010methoxyflavan (Fa131) on wild\u2010type and mutated GABA<jats:sub>A<\/jats:sub>receptors.<\/jats:p><jats:p><jats:bold>KEY RESULTS<\/jats:bold>The newly identified flavan, 2<jats:italic>S<\/jats:italic>,3<jats:italic>S<\/jats:italic>\u2010<jats:italic>cis<\/jats:italic>3\u2010acetoxy\u20103\u2032,4\u2032\u2010dimethoxyflavan (Fa173), antagonized the potentiating actions of Fa131, etomidate and loreclezole at \u03b11\u03b22 and \u03b11\u03b22\u03b32L GABA<jats:sub>A<\/jats:sub>receptors. Furthermore, Fa173 blocked the potentiation of GABA responses by high, but not low, concentrations of diazepam, but did not block the potentiation induced by propofol, the neurosteroid THP or the barbiturate thiopental. Mutational studies on \u2018anaesthetic\u2010influencing\u2019 residues showed that, compared with wild\u2010type GABA<jats:sub>A<\/jats:sub>receptors, \u03b11M236W\u03b22\u03b32L and \u03b11\u03b22N265S\u03b32L receptors are resistant to potentiation by etomidate, loreclezole and Fa131.<\/jats:p><jats:p><jats:bold>CONCLUSIONS AND IMPLICATIONS<\/jats:bold>Fa173 is a selective antagonist that can be used for allosteric modulation of GABA<jats:sub>A<\/jats:sub>receptors. Flavan\u20103\u2010ol derivatives are potential ligands for etomidate\/loreclezole\u2010related binding sites at GABA<jats:sub>A<\/jats:sub>receptors and the low\u2010affinity effects of diazepam are mediated via the same site.<\/jats:p>","DOI":"10.1111\/j.1476-5381.2011.01615.x","type":"journal-article","created":{"date-parts":[[2011,8,1]],"date-time":"2011-08-01T16:18:32Z","timestamp":1312215512000},"page":"965-977","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Flavan\u20103\u2010ol esters: new agents for exploring modulatory sites on GABA<sub>A<\/sub>receptors"],"prefix":"10.1111","volume":"165","author":[{"given":"Sebastian P","family":"Fernandez","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nasiara","family":"Karim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenneth 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