Design, Synthesis, and Biological Assessment of Novel Vanillin-Isoxazole Derivatives as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptor

Abstract

The homomeric α7 nicotinic acetylcholine receptor (α7 nAChR) is a cation-permeable pentameric ligand-gated channel present in the nervous system and non-neuronal cells. α7 nAChRs are highly expressed in brain regions critical for cognition and memory, such as the hippocampus and cerebral cortex. Therefore, enhancing its function with positive allosteric modulators (PAMs) is a promising therapeutic approach for treating cognitive deficits and neurodegenerative disorders. Continuing with our previous work in the search for novel PAMs of α7 nAChR, this study presents the synthesis and biological evaluation of novel isoxazole-vanillin derivatives exhibiting α7-PAM activity. Isoxazole derivatives with functional α7-PAM activity were identified by determining the effects of the synthetic compounds at different concentrations on the properties of the single channels elicited by ACh (100 μM). We found that only vanillin-derived isoxazoles (containing the 4-hydroxy-3-methoxy fragment) exhibited α7-enhancing activity in comparison to isoxazoles derived from dihydroxy- or dimethoxybenzaldehydes. The use of different substituted phenylacetylenes allowed us to create a small library of compounds with α7-PAM activity.

Keywords

• nicotinic receptors
• allosteric modulation
• α7-PAM
• isoxazoles