{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T17:28:33Z","timestamp":1787160513761,"version":"build-2736575974"},"reference-count":22,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T00:00:00Z","timestamp":1465776000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Novel esters of \u03b3-aminobutyric acid (GABA) with monocyclic terpenes were synthesized via Steglich esterification and characterized by 1H-NMR, IR and mass spectral studies. Their anticonvulsant, analgesic and anti-inflammatory activities were evaluated by a PTZ-induced convulsion model, AITC-induced hyperalgesia and AITC-induced paw edema, respectively. All studied esters, as well as their parent terpenes, were found to produce antinociceptive effects in the AITC-induced model and attenuate acute pain more than the reference drug benzocaine after their topical application. GABA esters of l-menthol and thymol were also shown to exceed the reference drug ibuprofen in their ability to decrease the inflammatory state induced by intraplantar injection of the TRPA1 activator AITC. The present findings indicate that GABA esters of carvacrol and guaiacol are not a classical prodrug and possess their own pharmacological activity. Prolonged antiseizure action of the ester based on the amino acid and guaiacol (200 mg\/kg) was revealed at 24 h after oral administration. Furthermore, orally co-administered gidazepam (1 mg\/kg) and GABA esters of l-menthol, thymol and carvacrol produce synergistic seizure prevention effects.<\/jats:p>","DOI":"10.3390\/ph9020032","type":"journal-article","created":{"date-parts":[[2016,6,13]],"date-time":"2016-06-13T10:29:22Z","timestamp":1465813762000},"page":"32","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Synthesis and Pharmacological Properties of Novel Esters Based on Monocyclic Terpenes and GABA"],"prefix":"10.3390","volume":"9","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3201-7961","authenticated-orcid":false,"given":"Mariia","family":"Nesterkina","sequence":"first","affiliation":[{"name":"Department of Pharmaceutical Chemistry, I.I. Mechnikov Odessa National University, Odessa 65026, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8929-8701","authenticated-orcid":false,"given":"Iryna","family":"Kravchenko","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutical Chemistry, I.I. Mechnikov Odessa National University, Odessa 65026, Ukraine"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2016,6,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1117","DOI":"10.1021\/cn500094a","article-title":"Transient receptor potential channels as targets for phytochemicals","volume":"5","author":"Premkumar","year":"2014","journal-title":"ACS Chem. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1146\/annurev.biochem.75.103004.142819","article-title":"TRP channels","volume":"76","author":"Venkatachalam","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1016\/j.pharmthera.2004.11.008","article-title":"Contribution of natural products to the discovery of the transient receptor potential (TRP) channels family and their functions","volume":"106","author":"Calixto","year":"2005","journal-title":"Pharmacol. Ther."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2803","DOI":"10.1111\/bph.12602","article-title":"Menthol enhances phasic and tonic GABAA receptor-mediated currents in midbrain periaqueductal grey neurons","volume":"171","author":"Lau","year":"2014","journal-title":"Br. J. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"308","DOI":"10.4236\/ojanes.2014.412044","article-title":"Comparative interactions of anesthetic alkylphenols with lipid membranes","volume":"4","author":"Tsuchiya","year":"2014","journal-title":"Open J. Anesthesiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"487","DOI":"10.2174\/1568007043336716","article-title":"GABA puts a stop to pain","volume":"3","author":"Jasmin","year":"2004","journal-title":"Curr. Drug Targets CNS Neurol. Disord."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1016\/j.cell.2015.01.022","article-title":"GABA blocks pathological but not acute TRPV1 pain signals","volume":"160","author":"Hanack","year":"2015","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/s10600-016-1604-9","article-title":"Synthesis and anticonvulsant activity of menthyl \u03b3-aminobutyrate","volume":"52","author":"Nesterkina","year":"2016","journal-title":"Chem. Nat. Compd."},{"key":"ref_9","first-page":"60","article-title":"Thymol ester gamma-aminobutyric acid: Synthesis and anticonvulsant activity","volume":"20","author":"Nesterkina","year":"2015","journal-title":"ONU Herald."},{"key":"ref_10","first-page":"725","article-title":"Activation of carboxylic acids with pyrocarbonates. Esterification of N-acylamino acids with secondary alcohols using di-tret-butylpyrocarbonate\u2014Pyridine as the condensing reagents","volume":"11","author":"Pozdnev","year":"1985","journal-title":"Russ. J. Bioorg. Chem."},{"key":"ref_11","first-page":"601","article-title":"Transient receptor potential channels as therapeutic targets","volume":"10","author":"Moran","year":"2011","journal-title":"Nature"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Nesterkina, M.V., and Kravchenko, I.A. (2016). Analgesic activity of novel GABA esters after transdermal delivery. Nat. Prod. Commun., in press.","DOI":"10.1177\/1934578X1601101001"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"183","DOI":"10.2174\/157015906778019482","article-title":"The emerging role of TRP channels in mechanisms of temperature and pain sensation","volume":"4","author":"Story","year":"2006","journal-title":"Curr. Neuropharmacol."},{"key":"ref_14","first-page":"763","article-title":"The vanilloid receptor TRPV1 is activated and sensitized by local anesthetics in rodent sensory neurons","volume":"118","author":"Leffler","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1111\/jns5.12010","article-title":"Mechanisms underlying transient receptor potential ankyrin 1 (TRPA1)-mediated hyperalgesia and edema","volume":"18","author":"Teixeira","year":"2013","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep00380","article-title":"TRPA1 contributes to the acute inflammatory response and mediates carrageenan-induced paw edema in the mouse","volume":"2","author":"Moilanen","year":"2012","journal-title":"Sci. Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"663","DOI":"10.2174\/0929867320666131119152201","article-title":"Pathophysiogenesis of mesial temporal lobe epilepsy: Is prevention of damage antiepileptogenic?","volume":"21","author":"Curia","year":"2014","journal-title":"Curr. Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/0920-1211(92)90030-W","article-title":"Chemical models of epilepsy with some reference to their applicability in the development of anticonvulsants","volume":"12","author":"Deyn","year":"1992","journal-title":"Epilepsy Res."},{"key":"ref_19","first-page":"6566","article-title":"Carvacrol, (\u2212)-borneol and citral reduce convulsant activity in rodents","volume":"9","author":"Oliveira","year":"2010","journal-title":"Afr. J. Biotechnol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.neuropharm.2005.07.009","article-title":"Allosteric positive interaction of thymol with the GABAA receptor in primary cultures of mouse cortical neurons","volume":"50","author":"Garcia","year":"2006","journal-title":"Neuropharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1966","DOI":"10.1080\/00397910802627076","article-title":"Facile synthesis of second-generation dendrons with an orthogonal functional group at the focal point","volume":"39","author":"Cheedarala","year":"2009","journal-title":"Synth. Commun."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1631\/jzus.B1400189","article-title":"Antinociceptive activity of transient receptor potential channel TRPV1, TRPA1, and TRPM8 antagonists in neurogenic and neuropathic pain models in mice","volume":"16","author":"Filipek","year":"2015","journal-title":"J. Zhejiang Univ. Sci. B"}],"container-title":["Pharmaceuticals"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1424-8247\/9\/2\/32\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T19:25:20Z","timestamp":1760210720000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1424-8247\/9\/2\/32"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,6,13]]},"references-count":22,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2016,6]]}},"alternative-id":["ph9020032"],"URL":"https:\/\/doi.org\/10.3390\/ph9020032","relation":{},"ISSN":["1424-8247"],"issn-type":[{"value":"1424-8247","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,6,13]]}}}