The influence of kavapyrones from Piper methysticum Forst. on the GABAA receptor was demonstrated using radioreceptor assays. Both the dienolide yangonin and the genuine enolide enantiomers (+)-kavain, (+)-dihydrokavain, (+)-methysticin, and (+)-dihydromethysticin enhanced the specific binding of [3H]bicuculline methochloride ([3H]BMC). The kavapyrones have been investigated at assay concentrations between 100 microM and 10 nM. (+)-Kavain, (+)-methysticin and (+)-dihydromethysticin showed maximal enhancements of 18% to 28% at a concentration of 0.1 microM, whereas a 100-fold concentration of (+)-dihydrokavain revealed a similar modulatory activity of 22%. In the presence of 1 microM yangonin an increase of about 21% of the specific [3H]BMC binding was observed. Desmethoxyyangonin did not alter the binding behavior of the GABAA-receptor. A structure comparison of desmethoxyyangonin and yangonin indicated that the aromatic methoxy group was of particular importance for the modulatory activity. In contrast, the substitution pattern of the aromatic ring did not influence the modulatory activity of the enolides in a decisive manner. A structure comparison of desmethoxyyangonin and (+)-kavain revealed that an angular lactone ring was an important structure requirement. Both the enolides and the dienolides did not inhibit the specific binding of [3H]flunitrazepan. Thus, the influence on the GABAA receptor was not based upon an interaction of these kavapyrones with the benzodiazepine receptor.