Cation –π Interaction Key to Nicotine Binding

High affinity binding of nicotine to subtype α4β2 nicotinic acetylcholine receptors in the brain is thought to be critical for nicotine addiction, but the reason for the higher affinity of nicotine at these receptors than at muscle receptors has been difficult to explain, especially given the similarity between the two types of receptors. If nicotine activated muscle receptors as strongly as it does brain receptors, smoking would cause unbearable, and possibly fatal, muscle contractions. Dougherty and colleagues, writing in the journal Nature, have now described a strong cation-π interaction between nicotine and a tryptophan residue, TrpB, in the brain α4β2 receptor. cation pi interactionThis key interaction is not formed between nicotine and muscle receptors even though the residues around the binding site, including the key tryptophan, are identical in brain and muscle receptors. A point mutation close to TrpB that differentiates α4β2 and muscle receptors appears to affect the exact shape of the binding sites and allows nicotine to interact more strongly with TrpB in the brain receptor. The new insight into differences in binding affinities may help in the development of drugs that target specific nicotinic acetylcholine receptors and, since more than 25% of all tryptophans are believed to be involved in cation-π interactions, may also have relevance for other drug classes. Energies for cation-π interactions, which are non-covalent interactions between the face of an electron-rich π-system and an adjacent cation, are comparable to those for hydrogen bonds.