Nicotine binding to brain receptors requires a strong cation–π interaction

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