Design, Synthesis, and Functional Evaluation of a Novel Series of Phosphonate-Functionalized 1,2,3-Triazoles as Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors

Abstract

The α7 nicotinic acetylcholine receptor is a pentameric ligand-gated ion channel widely distributed in the central nervous system, mainly in the hippocampus and cortex. The enhancement of its activity by positive allosteric modulators (PAMs) is a promising therapeutic strategy for cognitive deficits and neurodegenerative disorders. With the aim of developing novel scaffolds with PAM activity, we designed and synthesized a series of phosphonate-functionalized 1,4-disubstituted 1,2,3-triazoles using supported copper nanoparticles as the cycloaddition reaction catalyst and evaluated their activity on α7 receptors by single-channel and whole-cell recordings. We identified several triazole derivatives that displayed PAM activity, with the compound functionalized with the methyl phosphonate group being the most efficacious one. At the macroscopic level, α7 potentiation was evidenced as an increase of the maximal currents elicited by acetylcholine with minimal effects on desensitization, recapitulating the actions of type I PAMs. At the single-channel level, the active compounds did not affect channel amplitude but significantly increased the duration of channel openings and activation episodes. By using chimeric and mutant α7 receptors, we demonstrated that the new α7 PAMs share transmembrane structural determinants of potentiation with other chemically nonrelated PAMs. To gain further insight into the chemical basis of potentiation, we applied structure−activity relationship strategies involving modification of the chain length, inversion of substituent positions in the triazole ring, and changes in the aromatic nucleus. Our findings revealed that the phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole is a novel pharmacophore for the development of therapeutic agents for neurological and neurodegenerative disorders associated with cholinergic dysfunction.

Side Groups Convert the α7 Nicotinic Receptor Agonist Ether Quinuclidine into a Type I Positive Allosteric Modulator

“…The magnitude of the increase of the burst duration is more similar to that observed in the presence of low-efficacy type I PAMs, such as 5-HI, than in the presence of the highly efficacious type II PAMs, such as PNU-120596. In contrast to what we detected for other PAMs, such as 5-HI, 52 flavonoids, 13 and phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole compounds, 56 the open state or that it does not exert any effect on desensitization, as expected for a type I PAM, since desensitization is the major determinant of α7 nAChR open channel lifetime. 53,57 Increasing the concentration of ligand 6 to 60 μM led to significantly reduced channel activity, with patches showing very low activity that did not allow further analysis (n = 11, N = 4), thus indicating an additional inhibitory effect.…”

“…The magnitude of the increase of the burst duration is more similar to that observed in the presence of low-efficacy type I PAMs, such as 5-HI, than in the presence of the highly efficacious type II PAMs, such as PNU-120596. In contrast to what we detected for other PAMs, such as 5-HI, flavonoids, and phosphonate-functionalized 1,4-disubstituted 1,2,3-triazole compounds, ligand 6 did not increase open duration. This may indicate either that it has a very low efficacy to stabilize the open state or that it does not exert any effect on desensitization, as expected for a type I PAM, since desensitization is the major determinant of α7 nAChR open channel lifetime. , …”

“…Increasing the concentration of ligand 6 to 60 μM led to significantly reduced channel activity, with patches showing very low activity that did not allow further analysis ( n = 11, N = 4), thus indicating an additional inhibitory effect. The decrease of the potentiation ability at high concentrations has been described for other α7 nAChR PAMs, including flavonoids and phosphonate-functionalized 1,2,3-triazoles. , …”

4R-Tobacco-Cembranoid is a Positive Allosteric Modulator of the Alpha7 Nicotinic Acetylcholine Receptor that modulates inflammation-induced thermal hypersensitivity in mice

“…Previous studies have shown that α7nAChRs modulate nociceptive responses (Hone and McIntosh 2018), with positive allosteric modulators decreasing injury-induced hypersensitivity (Freitas et al 2013, El Nebrisi et al 2018, Nielsen et al 2020). The next set of experiments aimed at testing the hypothesis that 4R-mediated increases in cholinergic signaling lead to decreases in injury-induced hypersensitivity in male mice.…”

Self-Cognizant Bionic Liquid Sensor for Pathogen Diagnosis

“…The particular form of the 1,2,3-triazole therapeutic agent that detects a specific biological target with dipole interactions and hydrogen bond is shown in Figure 3 . Protease inhibitors bind to a viral enzyme thereby precluding pathogen from replicating making agents such as 1,2,3-triazoles particularly suitable for use as a therapeutic agent that exhibits antiviral activities and pharmacophore biological properties against allergy [ 24 ].…”