Abstract

The alkaloids aristoteline (1), aristoquinoline (2), and aristone (3) were purified from the leaves of the Maqui tree Aristotelia chilensis and chemically characterized by NMR spectroscopy. The pharmacological activity of these natural compounds was evaluated on human (h) alpha 3 beta 4, alpha 3 beta 4, and alpha 7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results suggest that these alkaloids do not have agonistic, but inhibitory, activity on each receptor subtype. The obtained IC50 values indicate the following receptor selectivity: h alpha 3 beta 4 > h alpha 4 beta 2 >> h alpha 7. In the particular case of h alpha 3 beta 4 AChRs, 1 (0.40 +/- 0.20 mu M) and 2 (0.96 +/- 0.38 mu M) show higher potencies compared with 3 (167 +/- 3 mu M). Molecular docking and structure activity relationship results indicate that ligand lipophilicity is important for the interaction with the luminal site located close to the cytoplasmic side of the +/- ion channel between positions-2' and-4'. Compound 1 could be used as a molecular scaffold for the development of more potent noncompetitive inhibitors with higher selectivity for the h alpha 3 beta 4 AChR that could serve for novel addiction and depression therapies.