Exploring the nature of molecular recognition in nicotinic acetylcholine receptors.
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.
Schmitt
J D
JD
Research and Development, Targacept Inc., Bowman Gray Technical Center, 950 Reynolds Boulevard, Winston-Salem, North Carolina 27105, USA. schmitj@rjrt.com
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
D008024:Ligands; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D000109:Acetylcholine