Issue Date: March 9, 2009
Nicotine's Binding Mystery Solved
CALTECH CHEMISTS have solved the chemical mystery of why nicotine binds to acetylcholine receptors with high affinity in the brain but with low affinity in muscles. Such information will help researchers understand nicotine addiction and guide drug discovery efforts for diseases in which acetylcholine receptors are implicated, such as schizophrenia and Parkinson's disease, among many others.
More than a decade ago, Caltech chemist Dennis A. Dougherty and coworkers discovered that acetylcholine binds tightly to its receptors because of a cation-π interaction between a positively charged nitrogen in the ligand and the aromatic ring of a specific tryptophan in the receptor. Dougherty thought that nicotine would bind in a similar way because many acetylcholine receptors bind nicotine, but nicotine did not form a cation-π interaction with the muscle cell receptors Dougherty was studying.
"If the acetylcholine receptor of the neuromuscular junction were as sensitive to nicotine as the brain receptor, you couldn't smoke," Dougherty says. "Nicotine would just be a toxin."
Dougherty, Caltech neurobiologist Henry A. Lester, and coworkers now show that nicotine binding to acetylcholine receptors in the brain does involve a cation-π interaction (Nature, DOI: 10.1038/nature07768). They dissect the binding interaction by substituting fluorinated amino acid analogs in the binding site.
The difference in the binding behavior of nicotine in brain versus muscle receptors suggests that the molecule is located closer to the key tryptophan residue in brain receptors than that in muscle receptors. Because the binding site—known as the "aromatic box" because it consists of five aromatic amino acids arranged in the shape of a box with the lid removed—is the same in all acetylcholine receptors, Dougherty hypothesized that the key difference must be outside the binding site.
Previous work by other groups had suggested that a glycine residue outside the muscle receptor's binding site discourages the formation of a hydrogen bond between the receptor backbone and the ligand. When Dougherty replaced that glycine residue with a lysine, the muscle receptor bound nicotine tightly, just as the brain receptor does.
Dougherty thinks that this hydrogen bond slightly alters the shape of the aromatic box, moving the ligand closer to the tryptophan residue and turning on the cation-π interaction.
"The present findings are new and significant," especially for the design of drugs that are selective for specific types of acetylcholine receptors, says M. Novella Romanelli, a professor of medicinal chemistry at the University of Florence, in Italy, "since they correct and refine the models developed so far and can explain known, but somewhat puzzling, structure-activity relationship data on nicotine."
- Chemical & Engineering News
- ISSN 0009-2347
- Copyright © American Chemical Society