title: Exploring the nature of molecular recognition in nicotinic acetylcholine receptors.
abstract: 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- pi-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.
authors.affiliation: Research and Development, Targacept Inc., Bowman Gray Technical Center, 950 Reynolds Boulevard, Winston-Salem, North Carolina 27105, USA. schmitj@rjrt.com
authors.forename: J D
authors.initials: JD
authors.lastname: Schmitt
mesh_terms: D000109:Acetylcholine / Q000737:chemistry* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002626:Chemistry, Pharmaceutical; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009538:Nicotine / Q000737:chemistry* / Q000378:metabolism; D018722:Nicotinic Agonists / Q000145:classification / Q000378:metabolism; D018733:Nicotinic Antagonists / Q000145:classification / Q000378:metabolism; D020836:Protein Structure, Quaternary; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D000109:Acetylcholine