Exploring the Nature of Molecular Recognition in Nicotinic Acetylcholine Receptors

• Published in: Current medicinal chemistry Vol. 7; no. 8; pp. 749 - 800
• Main Author: SCHMITT, Jeffrey D.
• Format: Journal Article
• Language: English
• Published: Schiphol Bentham Science Publishers Ltd 01.08.2000; Bentham Science Publishers; Bentham Science
• Subjects: Acetylcholine - chemistry; Acetylcholine - metabolism; Animals; Binding Sites; Biological and medical sciences; Chemistry, Pharmaceutical; Cholinergic system; Entropy; Etiology; Ligands; Medical sciences; Models, Molecular; Molecular Structure; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Nicotine - chemistry; Nicotine - metabolism; Nicotinic Agonists - classification; Nicotinic Agonists - metabolism; Nicotinic Antagonists - classification; Nicotinic Antagonists - metabolism; nicotinic receptors; Pharmacology. Drug treatments; Protein Structure, Quaternary; Receptors, Nicotinic - chemistry; Receptors, Nicotinic - metabolism; Structure-Activity Relationship; Peripheral nervous system; Organic cation; Molecular structure; Aliphatic compound; Nitrogen heterocycle; Iminium compounds; Ligand; Central nervous system; Binding site; Review; Quaternary ammonium compound; Biological fixation; Cholinergic receptor; Structure activity relation; Affinity; Nicotinic receptor; Subtype; Recognition
• DOI: 10.2174/0929867003374660
• ISSN: 0929-8673

Nicotinic acetylcholine receptors (nAChRs) are the subject of ever increasing interest because of their presumed involvement in the etiology of numerous clinical disorders. Unfortunately, the absence of atomic-level structural data, as well as the pharmacological complexity of these receptors leaves many fundamental questions unanswered. An understanding of how ligands interact with the receptor and, in-turn, how these interactions lead to pharmacological effect is vital in the advancement of nAChR-based therapeutics. We will first explore physico-chemical themes that are evidenced to be of particular importance in nAChR molecular recognition; these are- p-cation interaction, conformational entropy and stereochemistry. The second objective of this review is an interpretive encapsulation of the extensive and disparate body of structure-activity data that now exists for nAChRs. Finally, this review will advocate a re-investigation of distance geometry based methods as well as the need for additional approaches in nicotinic receptor pharmacophore generation.