Chalcones as positive allosteric modulators of α7 nicotinic acetylcholine receptors: A new target for a privileged structure

• New positive allosteric modulators of α7 nicotinic receptors has been found.
• They are chalcones substituted with hydroxyl groups at defined locations.
• The most potent was 2,4,2′,5′-tetrahydroxychalcone, named compound 111.
• 111 showed its potential as neuroprotective, analgesic and cognitive enhancer.

The α7 acetylcholine nicotine receptor is a ligand-gated ion channel that is involved in cognition disorders, schizophrenia, pain and inflammation among other diseases. Therefore, the development of new agents that target this receptor has great significance. Positive allosteric modulators might be advantageous, since they facilitate receptor responses without directly interacting with the agonist binding site. Here we report the search for and further design of new positive allosteric modulators having the relatively simple chalcone structure. From the natural product isoliquiritigenin as starting point, chalcones substituted with hydroxyl groups at defined locations were identified as optimal and specific promoters of α7 nicotinic function. The most potent compound (2,4,2′,5′-tetrahydroxychalcone, 111) was further characterized showing its potential as neuroprotective, analgesic and cognitive enhancer, opening the way for future developments around the chalcone structure.

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