Abstract

Alzheimer’s disease (AD) is a neurodegenerative disorder marked by the accumulation of ?-amyloid (A?) peptides, which disrupt neuronal homeostasis through their neurotoxic effects. A? aggregates interfere with synaptic function by interacting with nicotinic acetylcholine receptors (nAChRs), particularly the ?7 subtype, thereby impairing cholinergic signaling, which is crucial for cognition and memory. Pharmacological advancements have identified Positive Allosteric Modulators (PAMs) as promising therapeutic agents to counteract A? neurotoxicity. PAMs enhance nAChR activity by binding to allosteric sites, thereby reducing A?-induced neurotoxicity without competing with acetylcholine. This study evaluates 3-((6-(phenylethynyl)pyridine-3-yl)oxy)quinuclidine (EQ-04), a novel PAM with high selectivity for the ?7 nAChR subtype, demonstrating neuroprotective potential. In vitro analyses using PC-12 cells evaluated the cytotoxic and neuroprotective properties of EQ-04. Cytotoxicity assays confirmed EQ-04’s safety, showing no adverse effects on cell viability across concentrations. EQ-04 significantly enhanced cell viability by 37% at 1 nM against A? toxicity and inhibited A? aggregation. These findings highlight the potential of EQ-04 as a neuroprotective agent for Alzheimer’s disease (AD) therapy, warranting further investigation into its pharmacokinetics and in vivo efficacy. © 2025 The Authors. Published by American Chemical Society