title: Use of calculated cation-pi binding energies to predict relative strengths of nicotinic acetylcholine receptor agonists.
abstract: Agonists and antagonists of the nicotinic acetylcholine receptor (nAChR) are used to treat nicotine addiction, neuromuscular disorders, and neurological diseases. In designing small molecule therapeutics with the nAChR as a target, it is useful to identify chemical parameters that correlate with ability to activate the receptor. Previous studies have shown that cation-pi interactions at the transmitter binding sites of the nAChR are important for receptor activation by strong agonists such as acetylcholine. We hypothesized that a calculated estimate of cation-pi binding ability could be used to predict the efficiency for channel opening (i.e., the gating efficiency) associated with activation of the acetylcholine receptor by a series of structurally related organic cations. We demonstrate that the calculated cation-pi energy is strongly correlated with gating efficiency but only weakly correlated with closed-state binding affinity. Our results suggest that cation-pi interactions contribute significantly to the open-state affinity of these cations and that the calculated cation-pi energy will be a useful parameter for designing nAChR agonists and antagonists.
authors.affiliation: Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 16, Room 573B, Cambridge, Massachusetts 02139, USA.
authors.forename: Mathew
authors.initials: M
authors.lastname: Tantama
authors.forename: Stuart
authors.initials: S
authors.lastname: Licht
mesh_terms: D001665:Binding Sites; D002412:Cations; D015195:Drug Design; D004583:Electrons; D008958:Models, Molecular; D008962:Models, Theoretical; D018722:Nicotinic Agonists / Q000737:chemistry*; D011978:Receptors, Nicotinic / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D002412:Cations; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic