Self-assembling cannabinomimetics: supramolecular structures of N-alkyl amides.
Certain fatty acid N-alkyl amides from the medicinal plant Echinacea activate cannabinoid type-2 (CB2) receptors. In this study we show that the CB2-binding Echinacea constituents dodeca-2E,4E-dienoic acid isobutylamide (1) and dodeca-2E,4E,8Z,10Z-tetraenoic acid isobutylamide (2) form micelles in aqueous medium. In contrast, micelle formation is not observed for undeca-2E-ene-8,10-diynoic acid isobutylamide (3), which does not bind to CB2, or structurally related endogenous cannabinoids, such as arachidonoyl ethanolamine (anandamide). The critical micelle concentration (CMC) range of 1 and 2 was determined by fluorescence spectroscopy as 200-300 and 7400-10000 nM, respectively. The size of premicelle aggregates, micelles, and supermicelles was studied by dynamic light scattering. Microscopy images show that compound 1, but not 2, forms globular and rod-like supermicelles with radii of approximately 75 nm. The self-assembling N-alkyl amides partition between themselves and the CB2 receptor, and aggregation of N-alkyl amides thus determines their in vitro pharmacological effects. Molecular mechanics by Monte Carlo simulations of the aggregation process support the experimental data, suggesting that both 1 and 2 can readily aggregate into premicelles, but only 1 spontaneously assembles into larger aggregates. These findings have important implications for biological studies with this class of compounds.
Raduner
Stefan
S
Department of Chemistry and Applied Biosciences, ETH Zurich, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich, Switzerland.
Bisson
William
W
Abagyan
Ruben
R
Altmann
Karl-Heinz
KH
Gertsch
Jürg
J
D000577:Amides / Q000737:chemistry* / Q000302:isolation & purification / Q000493:pharmacokinetics; D001095:Arachidonic Acids / Q000737:chemistry / Q000493:pharmacokinetics; D003511:Cyclohexanols / Q000494:pharmacology; D020900:Echinacea / Q000737:chemistry*; D063388:Endocannabinoids; D006801:Humans; D008954:Models, Biological; D015394:Molecular Structure; D010946:Plants, Medicinal / Q000737:chemistry*; D053284:Polyunsaturated Alkamides / Q000737:chemistry / Q000493:pharmacokinetics; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects*
D000577:Amides; D001095:Arachidonic Acids; D003511:Cyclohexanols; D063388:Endocannabinoids; D053284:Polyunsaturated Alkamides; D043885:Receptor, Cannabinoid, CB2; C054649:3-(2-hydroxy-4-(1,1-dimethylheptyl)phenyl)-4-(3-hydroxypropyl)cyclohexanol; C078814:anandamide