Nicotine Binding to Brain Receptors Requires a Strong Cation-π Interaction

Nicotine addiction begins with high-affinity binding of nicotine to acetylcholine (ACh) receptors in the brain. The end result is over 4,000,000 smoking-related deaths annually worldwide and the largest source of preventable mortality in developed countries. Stress reduction, pleasure, improved cognition, and other CNS effects are strongly associated with smoking. But, if nicotine activated ACh receptors found in muscle as potently as it does brain receptors, smoking would cause intolerable and perhaps fatal muscle contractions. Despite extensive pharmacological, functional, and structural studies of ACh receptors, the basis for the differential action of nicotine on brain vs. muscle ACh receptors has not been determined. Here we show that at the α4β2 brain receptors thought to underlie nicotine addiction, the high affinity of nicotine is the result of a strong cation-п interaction to a specific aromatic amino acid of the receptor, TrpB. In contrast, the low affinity of nicotine at the muscle-type receptor is largely due to the fact that this key interaction is absent, even though the immediate binding site residues, including the key TrpB, are identical in the brain and muscle receptors. At the same time a hydrogen bond from nicotine to the backbone carbonyl of TrpB is enhanced in the neuronal receptor relative to the muscle-type. A point mutation near TrpB that differentiates α4β2 and muscle-type receptors appears to influence the shape of the binding site, allowing nicotine to interact more strongly with TrpB in the neuronal receptor. ACh receptors are established therapeutic targets for Alzheimer’s disease, schizophrenia, Parkinson’s disease, smoking cessation, pain, attention deficit-hyperactivity disorder, epilepsy, autism, and depression1. Along with solving a chemical mystery in nicotine addiction, our results provide guidance for efforts to develop drugs that target specific types of nicotinic receptors.