Nicotine's Double Life

摘要

Nicotine's remarkable propensity for inducing addiction starts with its ability to bind to brain acetylcholine (ACh) receptors with high affinity. If it activated the ACh receptors in muscle, nearly identical to those in the brain, with similar efficiency, smoking would cause severe muscle contractions. That this doesn't happen has been a long-running pharmacological puzzle, now solved in an in-depth study of the chemistry of nicotine's interaction with the two receptor types. Binding to the a4 and β2 receptor subunits that underlie nicotine addiction involves both hydrogen bond formation and strong cation-π interaction between the positive charge of nicotine and a specific, conserved tryptophan residue. Muscle-type receptors also contain this tryptophan, but the cation-π interaction does not exist and the hydrogen bond is weaker. This appears to be due to differences in the overall shape of the binding pocket, associated with a single point mutation near the key tryptophan residue. As wells as solving a molecular mystery, these results provide guidance for the development of new analogues of nicotine for possible therapeutic use in neurological conditions and smoking cessation.