Natural Polyhydroxy Flavonoids, Curcuminoids, and Synthetic Curcumin Analogs as α7 nAChRs Positive Allosteric Modulators

The alpha 7 nicotinic acetylcholine receptor (alpha 7 nAChR) is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain, and inflammation. Allosteric modulation of this receptor might be advantageous to reduce the toxicity in comparison with full agonists. Our previous results obtained with some hydroxy-chalcones, which were identified as positive allosteric modulators (PAMs) of alpha 7 nAChR, prompted us to evaluate the potential of some structurally related naturally occurring flavonoids and curcuminoids and some synthetic curcumin analogues, with the aim of identifying new allosteric modulators of the alpha 7 nAChR. Biological evaluation showed that phloretin, demethoxycurcumin, and bis-demethoxicurcuming behave as PAMs of alpha 7 nAChR. In addition, some new curcumin derivatives were able to enhance the signal evoked by ACh; the activity values found for the tetrahydrocurcuminoid analog 23 were especially promising.

Automated summary

This study evaluated a range of natural products and synthetic compounds, finding that phloretin, demethoxycurcumin, and bis-demethoxicurcuming act as positive allosteric modulators (PAMs) of α7 nAChR; and some new curcumin derivatives have the ability to enhance ACh-evoked signal, with tetrahydrocurcuminoid analog 23 showing particularly promising activity values.