Nicotinic acetylcholine receptors-targeting drug discovery

Nicotinic acetylcholine receptors (nAChRs) are a family of pentameric ligand-gated ion channels with diverse subunit compositions and subtype-specific functional profiles, such as in neurotransmission and inflammatory modulation. The central involvement of nAChRs in neurological and psychiatric disorders has these receptors as compelling therapeutic targets, especially for nicotine addiction, Alzheimer's disease, schizophrenia, attention-deficit/hyperactivity disorder, and pain disorders. Recent advances in nAChRs structural biology have revealed detailed mechanisms of ligand binding at orthosteric and allosteric sites, and rational drug design leveraging natural toxin-derived peptides and small molecules have yielded many nAChR subtype-selective agonists, antagonists, and allosteric modulators. Despite clinical success with some candidate drugs like nicotine patch and varenicline for smoking cessation, broader therapeutic application has been limited by challenges in receptor selectivity, desensitization, and off-target effects. Here, we provide a concise overview of nAChR structural biology, outline the physiological and pathological significance of distinct receptor subtypes, and offer a comprehensive review of the progress in the discovery of nAChR-targeting ligands, either of natural toxins or small molecules, in preclinical conditions and their advances in clinical trials. We also discuss the prevailing challenges while underscoring emerging opportunities for future therapeutic innovation.