{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,25]],"date-time":"2026-10-25T02:58:40Z","timestamp":1792897120075,"version":"4.5.0"},"reference-count":162,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2022,3,8]],"date-time":"2022-03-08T00:00:00Z","timestamp":1646697600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Natural products can act as potential GABA modulators, avoiding the undesirable effects of traditional pharmacology used for the inhibition of the central nervous system such as benzodiazepines (BZD). Phenolics, especially flavonoids and phlorotannins, have been considered as modulators of the BZD-site of GABAA receptors (GABAARs), with sedative, anxiolytic or anticonvulsant effects. However, the wide chemical structural variability of flavonoids shows their potential action at more than one additional binding site on GABAARs, which may act either negatively, positively, by neutralizing GABAARs, or directly as allosteric agonists. Therefore, the aim of the present review is to compile and discuss an update of the role of phenolics, namely as pharmacological targets involving dysfunctions of the GABA system, analyzing both their different compounds and their mechanism as GABAergic modulators. We focus this review on articles written in English since the year 2010 until the present. Of course, although more research would be necessary to fully establish the type specificity of phenolics and their pharmacological activity, the evidence supports their potential as GABAAR modulators, thereby favoring their inclusion in the development of new therapeutic targets based on natural products. Specifically, the data compiled in this review allows for the directing of future research towards ortho-dihydroxy diterpene galdosol, the flavonoids isoliquiritigenin (chalcone), rhusflavone and agathisflavone (biflavonoids), as well as the phlorotannins, dieckol and triphlorethol A. Clinically, flavonoids are the most interesting phenolics due to their potential as anticonvulsant and anxiolytic drugs, and phlorotannins are also of interest as sedative agents.<\/jats:p>","DOI":"10.3390\/molecules27061770","type":"journal-article","created":{"date-parts":[[2022,3,9]],"date-time":"2022-03-09T01:53:54Z","timestamp":1646790834000},"page":"1770","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":54,"title":["Phenolics as GABAA Receptor Ligands: An Updated Review"],"prefix":"10.3390","volume":"27","author":[{"given":"Jos\u00e9-Luis","family":"R\u00edos","sequence":"first","affiliation":[{"name":"Departament de Farmacologia, Facultat de Farm\u00e0cia, Universitat de Val\u00e8ncia, Av. Vicent Andr\u00e9s Estell\u00e9s s\/n, Burjassot, 46100 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9541-9688","authenticated-orcid":false,"given":"Guillermo R.","family":"Schinella","sequence":"additional","affiliation":[{"name":"Facultad de Ciencias M\u00e9dicas, Universidad Nacional de La Plata, La Plata BA1900, Argentina"},{"name":"Instituto de Ciencias de la Salud, UNAJ-CICPBA, Florencio Varela BA1888, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In\u00e9s","family":"Moragrega","sequence":"additional","affiliation":[{"name":"Departament de Psicobiologia, Facultat de Psicologia, Universitat de Val\u00e8ncia, Av. Blasco Ib\u00e1\u00f1ez 21, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,3,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/S0021-9258(19)50926-7","article-title":"Free \u03b3-aminobutyric acid in brain","volume":"187","author":"Awapara","year":"1950","journal-title":"J. Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/S0021-9258(19)50929-2","article-title":"\u03b3-Aminobutyric acid in brain: Its formation from glutamic acid","volume":"187","author":"Roberts","year":"1950","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.2174\/1381612054021024","article-title":"GABAA receptor channel pharmacology","volume":"11","author":"Johnston","year":"2005","journal-title":"Curr. Pharm. 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