Aristoteline from Aristotella chilensis is a selective inhibitor of human α3β4 nicotinic acetylcholine receptors

PAZ, CRISTIAN; MARIN-MOSI, V; ORTELLS, MARCELO OSCAR; ARIAS, HUGO R.

Krakow

Congreso; The 44th FEBS Congress; 2019

The Federation of European Biochemical Societies

The alkaloids aristone, aristoteline, and aristoquinoline are purified from the leaves of the Maqui tree Aristotelia chilensis and chemically characterized by NMR spectroscopy. The pharmacological activity of these natural compounds is subsequently determined on human (h) α3β4, α4β2, and α7 nicotinic acetylcholine receptors (AChRs) by Ca2+ influx measurements. The results establish that these alkaloids do not have agonistic, but inhibitory, activity on any receptor subtype. The obtained IC50 values indicate the following receptor selectivity: hα3β4 > hα4β2 >> hα7. In the particular case of hα3β4 AChRs, aristoteline (0.40 ± 0.20 µM) and aristoquinoline (0.96 ± 0.38 µM) show higher potencies compared to aristoquinoline (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'. Aristoteline could be used as a molecular scaffold for the development of more potent noncompetitive inhibitors with higher selectivity for the hα3β4 AChR that could serve for novel addiction and depression therapies.