POTENTIAL NICOTINIC RECEPTOR ANTAGONISTS: CHEMISTRY, RATIONALE, AND RESEARCH ROADMAP

Background: Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that regulate a wide array of physiological functions, such as cognition, pain, and autonomic functions. Their pathological activity has been associated with numerous disorders, including addiction, neurodegenerative diseases, and chronic pain. In spite of the nAChR's central role in physiological and pathological conditions, there are few effective and selective nAChR antagonists under development, primarily because of the variety of receptor subtypes and complex functional roles. Objective: The objective of this study is to examine the current state of chemical agents acting as nicotinic receptor antagonists, to provide the scientific rationale for their development, and to establish a roadmap for moving forward in future research towards antagonists for clinical use. Methods: A thorough review of literature was conducted that looked at chemical structure, binding characteristics, and functional effects of existing and potential new nicotinic receptor antagonists. Comparisons were then made of selective receptor subtype properties, pharmacological properties, and possible use as a treatment to illustrate trends and obstacles. Results: Antagonistic activity at various nAChR subtypes is exhibited by diverse chemical classes including natural alkaloids, synthetic small molecules, or peptide-based components. Receptor modeling and high-throughput screening techniques have increased the number of selective antagonists; however, clinical translation is still hampered by low bioavailability, non-specific binding, and ever-changing subtype characterization. Conclusions: The evolution of selective nicotinic receptor antagonists is still a promising but complex one, and it would be beneficial to incorporate structural and pharmacological research progress to inform a targeted research agenda that will focus on specificity, improved drug-like properties, and stronger preclinical assessment in an effort to expedite the innovation of therapeutics.