Use of Calculated Cation-π Binding Energies to Predict Relative Strengths of Nicotinic Acetylcholine Receptor Agonists Export

@article{citeulike:3682387, abstract = {doi: 10.1021/cb800189y 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-π 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-π 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-π energy is strongly correlated with gating efficiency but only weakly correlated with closed-state binding affinity. Our results suggest that cation-π interactions contribute significantly to the open-state affinity of these cations and that the calculated cation-π energy will be a useful parameter for designing nAChR agonists and antagonists.}, author = {Tantama, Mathew and Licht, Stuart}, citeulike-article-id = {3682387}, citeulike-linkout-0 = {http://dx.doi.org/10.1021/cb800189y}, citeulike-linkout-1 = {http://pubs.acs.org/doi/abs/10.1021/cb800189y}, doi = {10.1021/cb800189y}, journal = {ACS Chemical Biology}, keywords = {agonists, bond, cation, pi, receptor, strengths, tanta08pdf}, month = {November}, number = {11}, pages = {693--702}, posted-at = {2008-11-25 01:48:55}, priority = {2}, title = {Use of Calculated Cation-π Binding Energies to Predict Relative Strengths of Nicotinic Acetylcholine Receptor Agonists}, url = {http://dx.doi.org/10.1021/cb800189y}, volume = {3}, year = {2008} }

TY - JOUR ID - citeulike:3682387 L3 - citeulike-article-id:3682387 N2 - doi: 10.1021/cb800189y 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-π 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-π 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-π energy is strongly correlated with gating efficiency but only weakly correlated with closed-state binding affinity. Our results suggest that cation-π interactions contribute significantly to the open-state affinity of these cations and that the calculated cation-π energy will be a useful parameter for designing nAChR agonists and antagonists. IS - 11 JF - ACS Chemical Biology EP - 702 TI - Use of Calculated Cation-π Binding Energies to Predict Relative Strengths of Nicotinic Acetylcholine Receptor Agonists VL - 3 SP - 693 KW - agonists KW - bond KW - cation KW - pi KW - receptor KW - strengths KW - tanta08pdf AU - Tantama, Mathew AU - Licht, Stuart PY - 2008/11/21/ UR - http://dx.doi.org/10.1021/cb800189y ER -