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

Author

Listed:
  • Xinan Xiu

    (Divisions of Chemistry and Chemical Engineering and,)

  • Nyssa L. Puskar

    (Divisions of Chemistry and Chemical Engineering and,)

  • Jai A. P. Shanata

    (Divisions of Chemistry and Chemical Engineering and,)

  • Henry A. Lester

    (Biology, California Institute of Technology, 1200 East California Boulevard, Pasadena, California 91125, USA)

  • Dennis A. Dougherty

    (Divisions of Chemistry and Chemical Engineering and,)

Abstract

Nicotine's double life 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 α4 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.

Suggested Citation

  • Xinan Xiu & Nyssa L. Puskar & Jai A. P. Shanata & Henry A. Lester & Dennis A. Dougherty, 2009. "Nicotine binding to brain receptors requires a strong cation–π interaction," Nature, Nature, vol. 458(7237), pages 534-537, March.
    • Handle: RePEc:nat:nature:v:458:y:2009:i:7237:d:10.1038_nature07768
    DOI: 10.1038/nature07768
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    Cited by:

    1. Xinming Xia & Feng Zhou & Jing Xu & Zhongteng Wang & Jian Lan & Yan Fan & Zhikun Wang & Wei Liu & Junlang Chen & Shangshen Feng & Yusong Tu & Yizhou Yang & Liang Chen & Haiping Fang, 2022. "Unexpectedly efficient ion desorption of graphene-based materials," Nature Communications, Nature, vol. 13(1), pages 1-7, December.

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