title: Pharmacological actions of thymol and an analogue at GABAB autoreceptors.
abstract: GABAB autoreceptors inhibit release of GABA from GABAergic nerve terminals. Agonists of these receptors (e.g. baclofen) inhibit, whereas antagonists (e.g. (+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; Sch 50911) enhance release of the transmitter. The actions of thymol (2-isopropyl-5-methylphenol) and the structurally related compound 2-tert-butyl-4-methylphenol, (4MP) on the release of [(3) H]-GABA were examined in rat neocortical slices where the GABAergic nerves had been preloaded with [(3) H]-GABA and subsequently stimulated electrically on two occasions (S1 and S2 ). Test agents, baclofen and Sch 50911 were added to the superfusion medium prior to the second period of stimulation (S2 ). Stimulation-induced overflow (SIO) of [(3) H]-GABA as a consequence of these stimulations (SIO1 and SIO2 ) were calculated and the effects of agents determined by comparing the SIO2 /SIO1 ratio in the presence of each agent with that in control tissue. Thymol potentiated the release of [(3) H]-GABA (EC50 170 μmol/L), an action reversed by baclofen (2 μmol/L). Baclofen alone had little effect on GABA release. Release of [(3) H]-GABA was inhibited by 4MP (IC50 3 μmol/L) and this effect was blocked by Sch 50911 (10 μmol/L). Alone, Sch 50911 markedly potentiated the release of GABA. These results imply that 4MP is an agonist of GABAB autoreceptors; however, further studies are needed to confirm that thymol is indeed a GABAB autoreceptor antagonist. Of interest are structural differences in these agents. Thymol has a propyl group in the ortho position relative to the phenolic hydroxyl, whereas in 4MP this is a butyl group and the methyl group moves from position 5 to 4. Whether one or both of these changes was responsible for the above actions is unknown.
authors.affiliation: School of Dentistry, Faculty of Health Sciences, The University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: David As
authors.initials: DA
authors.lastname: Parker
authors.forename: Victor
authors.initials: V
authors.lastname: Marino
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ong
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000819:agonists* / Q000037:antagonists & inhibitors*; D001418:Baclofen / Q000494:pharmacology; D002084:Butylated Hydroxytoluene / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018755:GABA Agonists / Q000494:pharmacology; D058788:GABA-B Receptor Antagonists / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D019579:Neocortex / Q000187:drug effects / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D051381:Rats; D018080:Receptors, GABA-B / Q000378:metabolism*; D013943:Thymol / Q000737:chemistry / Q000494:pharmacology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C095804:(+)-(S)-5,5-dimethylmorpholinyl-2-acetic acid; D017660:Autoreceptors; D018755:GABA Agonists; D058788:GABA-B Receptor Antagonists; D009025:Morpholines; D010636:Phenols; D018080:Receptors, GABA-B; D002084:Butylated Hydroxytoluene; D013943:Thymol; D005680:gamma-Aminobutyric Acid; D001418:Baclofen; C054527:2-tert-butyl-4-methylphenol
keywords: GABA release; GABAB autoreceptors; baclofen; rat brain slices; thymol