Nicotinic acetylcholine receptors (nAChR) are ligand-gated ion channels formed by the assembly of five subunits. Receptor activity could be subjected to both positive and negative modulation at allosteric sites by endogenous neurotransmitters as well as synthetic ligands such as steroids, bivalent cations, alcohols, and a range of drugs. The subtype of α7 nAChR has been considered a potential therapeutic target for Alzheimer’s disease, schizophrenia, and other neurological and psychiatric disorders. In this work, we present the synthesis of a novel series of phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles with potential activity over α7 AChR.
These compounds were synthesized through the copper-catalyzed Huisgen 1,3-dipolar cycloaddition of organic azides and alkynes. Copper nanoparticles (CuNPs) immobilized on different supports were prepared using the CuCl2-Li-DTBB reducing system previously reported by our group. In our first studies, we determined that CuNPs over activated carbon were the most efficient catalyst in the reaction between 1-(azidomethyl)naphthalene and propargyl alcohol.
The employment of propargyl alcohol as alkyne allowed us further derivatizations on this triazole in order to obtain a small library of compounds which were tested as positive allosteric modulators (PAMs) of nAChR. We have found that the ones functionalized with phosphonates moieties have shown the desired activity, whereby we decided to extend the family of compounds functionalized with phosphorus moieties.