Alkaloids Purified from Aristotelia chilensis Inhibitthe Human α3β4 Nicotinic Acetylcholine Receptorwith Higher Potencies Compared with the Human α4β2 andα7 Subtypes

The alkaloids aristoteline (1), aristoquinoline (2), and aristone (3) were purified from the leaves of the Maqui tree Aristotelia chilensisand chemically characterized by NMR spectroscopy. The pharmacological activity of these natural compounds was evaluated on human (h) α3β4, α4β2, and α7 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: hα3β4 > hα4β2 ≫ hα7. In the particular case of hα3β4 AChRs, 1 (0.40 ± 0.20 μM) and 2 (0.96 ± 0.38 μM) show higher potencies compared with 3 (167 ± 3 μM). 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 hα3β4 ion channel between positions -2′ and -4′. Compound 1 could be used as a molecular scaffold for the development of ...