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

The α7 nicotinic acetylcholine receptor (α7 nAChR), a pentameric ligand-gated ion channel, is widely distributed throughout the central nervous system, particularly in the hippocampus and cortex. Enhancing its function using positive allosteric modulators (PAMs) represents a promising therapeutic approach for treating cognitive deficits and neurodegenerative disorders.

Continuing with our previous work in the search for novel allosteric modulators of α7 nAChR, this study presents the synthesis and biological evaluation of novel isoxazole-vanillin derivatives exhibiting α7-PAM activity.

The one-pot synthesis of 3,5-disubstituted isoxazoles were carried out through the cycloaddition reaction involving in situ generated nitrile oxides from different benzaldehydes and terminal alkynes generated from different benzaldehydes and terminal alkynes, catalyzed by supported copper nanoparticles (CuNPs). For the biological evaluation, single-channel currents were recorded from cells expressing human α7 wild type activated by acetylcholine (ACh). Isoxazole derivatives with functional α7-PAM activity were identified at the single-channel level, measuring currents in the presence of ACh (100 μM) and the synthetic compounds at different concentrations.

Upon evaluating the compounds, 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.