A Small Library of 1,2,3‐Triazole Analogs of CAP‐55: Synthesis and Binding Affinity at Nicotinic Acetylcholine Receptors

Abstract

Alpha7 nicotinic acetylcholine receptor is emerging as a central regulator in inflammatory processes, as documented by increasing studies reported in the literature. For instance, the activation of this nicotinic receptor subtype in resident macrophages inhibits the production of pro-inflammatory cytokines, thereby attenuating local inflammatory responses, and may open a new window in the treatment of chronic inflammatory disease, such as Crohn's disease, rheumatoid arthritis, psoriasis, and asthma. In continuation of our ongoing research for the development of new cholinergic drug candidates, we selected the nicotine derivative CAP55, which was previously shown to exert anti-inflammatory effects via nicotinic stimulation, as a suitable compound for lead optimization. Through the isosteric replacement of its 3,5-disubstituted 4,5-dihydroisoxazole core with a 1,4-disubstituted 1,2,3-triazole ring, we could rapidly generate a small library of CAP55-related analogs via a one-pot copper(I)-catalyzed azide-alkyne cycloaddition. Receptor binding assays at nAChRs led to the identification of two promising derivatives, compounds 4 and 10, worthy of further pharmacological studies.

Synthesis of a Novel Series of Phosphonate-Functionalized 1,2,3-Triazoles as Potential Candidates for Allosteric Modulation of α7 Nicotinic Acetylcholine Receptors

“…Frequently, isosteric replacement of this heterocycles, or amide linkers, with triazole rings allows the efficient generation of small libraries of ligands for nAChR via one-pot copper(I)-catalyzed azidealkyne cycloaddition. In this way, several triazole-containing agonists of nAChR were synthesized [4]. 1,2,4-triazoles are also present in structures acting over nicotinic receptors.…”