Alkamides and a neolignan from Echinacea purpurea roots and the interaction of alkamides with G-protein-coupled cannabinoid receptors

Three alkamides and nitidanin diisovalerianate were identified, together with 14 known alkamides and one sesquiterpene from the roots of Echinacea purpurea. Their interaction with G-protein-coupled cannabinoid receptors were examined. [Display omitted] . ► Four natural products, three alkamides and one neolignan, were identified in the roots of Echinacea purpurea. ► Four further known alkamides and one sesquiterpene were detected for the first time in this species. ► Ten known E. purpurea alkamides were isolated. ► Their cannabinoid receptor activity in [ 35S]GTPγS-binding assay were investigated on rat brain membrane preparations. ► Both partial and inverse agonist compounds were identified. Multiple chromatographic separations of the CHCl 3-soluble extract of the roots of Echinacea purpurea led to the isolation of 19 compounds. Four natural products, three alkamides and nitidanin diisovalerianate, were identified, and five further compounds were detected for the first time in this species. Additionally, 10 known E. purpurea metabolites were isolated. The structures were determined by mass spectrometry and advanced 1D and 2D NMR techniques. The bioactivity of the isolated compounds was studied in [ 35S]GTPγS-binding experiments performed on rat brain membrane preparations. Both partial and inverse agonist compounds for cannabinoid (CB1) receptors were identified among the metabolites, characterized by weak to moderate interactions with the G-protein signaling mechanisms. The G-protein-modulating activities of the Echinacea compounds are rather far from the full agonist effects seen with the CB1 receptor agonist reference compound arachidonyl-2′-chloroethylamide (ACEA). However, upon coadministration with ACEA, a number of them proved capable of inhibiting the stimulation of the pure agonist, thereby demonstrating cannabinoid receptor antagonist properties.