Using Physical Chemistry To Differentiate Nicotinic from Cholinergic Agonists at the Nicotinic Acetylcholine Receptor
- 2 December 2004
- journal article
- research article
- Published by American Chemical Society (ACS) in Journal of the American Chemical Society
- Vol. 127 (1) , 350-356
- https://doi.org/10.1021/ja0461771
Abstract
The binding of three distinct agonistsacetylcholine (ACh), nicotine, and epibatidineto the nicotinic acetylcholine receptor has been probed using unnatural amino acid mutagenesis. ACh makes a cation−π interaction with Trp α149, while nicotine employs a hydrogen bond to a backbone carbonyl in the same region of the agonist binding site. The nicotine analogue epibatidine achieves its high potency by taking advantage of both the cation−π interaction and the backbone hydrogen bond. A simple structural model that considers only possible interactions with Trp α149 suggests that a novel aromatic CH···OC hydrogen bond further augments the binding of epibatidine. These studies illustrate the subtleties and complexities of the interactions between drugs and membrane receptors and establish a paradigm for obtaining detailed structural information.Keywords
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