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.
The results from your paper are exciting. Thank you for a nice piece of work. Which binding site of nAChRs do you envision for your compounds? What is the starting point in the design of your ligands? Do you consider the triazole cycle and isoxazole cycle as bioisosteric replacements for the acid group?
Dr. Yulia Volkova
Thank you very much for your interest in our work. The alpha 7 nicotinic receptor presents different allosteric sites, so we cannot ascertain to which of them our compounds bind definitively. In other cases, we have been able to determine binding to the transmembrane domain using modified receptors (chimeras), and we hope to do the same with these isoxazole derivatives.
The design of our compounds was based on previous studies where it was determined that different types of flavonoids can allosterically modulate the alpha 7 receptor. This is why we started working with hydroxylated aldehydes. Additionally, our group is dedicated to the development of heterogeneous nanocatalysis methodologies, specifically for click-type reactions, which is why we work with 3,5-isoxazole and 1,2,3-triazole derivatives.
Finally, it is known that there are no alpha 7 PAMs that are charged species at physiological pH, so we do not use carboxylic acids for the synthesis of new PAMs. We believe that the tetrazole ring could be a better bioisostere of the carboxyl group; currently, our group is developing a method for obtaining this heterocycle.
Best regards,
Dr. Santiago Stabile
