Cation-pi interactions: Difference between revisions
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Like acetylcholine, nicotine has a cationic nitrogen when the pH is neutral or acidic. This occurs in nicotine's 5-membered methylpyrrolidine ring (see [http://en.wikipedia.org/wiki/Nicotine nicotine structure]), which has a pK<sub>a</sub> of 8.0<ref>In contrast, the 6-membered pyridine ring has a pK<sub>a</sub> of 3.1, so is uncharged at neutral pH. The uncharged or ''free base'' form of nicotine is more volatile than the charged form. Cigarette manufacturers have long added ammonia to tobacco to increase absorption of nicotine by smokers. See Summerfield, 1999 cited elsewhere for details.</ref><ref>Summerfield, J. H. An acid-base chemistry example: conversion of nicotine. J. Chem. Ed. 76:1397-8 (1999).</ref>. | Like acetylcholine, nicotine has a cationic nitrogen when the pH is neutral or acidic. This occurs in nicotine's 5-membered methylpyrrolidine ring (see [http://en.wikipedia.org/wiki/Nicotine nicotine structure]), which has a pK<sub>a</sub> of 8.0<ref>In contrast, the 6-membered pyridine ring has a pK<sub>a</sub> of 3.1, so is uncharged at neutral pH. The uncharged or ''free base'' form of nicotine is more volatile than the charged form. Cigarette manufacturers have long added ammonia to tobacco to increase absorption of nicotine by smokers. See Summerfield, 1999 cited elsewhere for details.</ref><ref>Summerfield, J. H. An acid-base chemistry example: conversion of nicotine. J. Chem. Ed. 76:1397-8 (1999).</ref>. | ||
In 1998, Zhong ''et al.'' (with Dougherty)<ref name="zhong">PMID: 9770444</ref> provided evidence that the [http://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor cation in acetylcholine] engages in a cation-pi interaction with Trp149 in the receptor, making an important contribution to the binding affinity. In 2002, Beene ''et al.'' (with Dougherty)<ref name="XD" /> provided evidence that no such cation-pi interaction is involved when nicotine binds to the muscle-type receptor, thus accounting in part for the lower affinity. | In 1998, Zhong ''et al.'' (with Dougherty)<ref name="zhong">PMID: 9770444</ref> provided evidence that the [http://en.wikipedia.org/wiki/Nicotinic_acetylcholine_receptor cation in '''acetylcholine'''] engages in a cation-pi interaction with Trp149 in the '''neuronal-type''' receptor, making an important contribution to the binding affinity. In 2002, Beene ''et al.'' (with Dougherty)<ref name="XD" /> provided evidence that no such cation-pi interaction is involved when '''nicotine''' binds to the '''muscle-type''' receptor, thus accounting in part for the lower affinity. In 2009, Xiu ''et al.''<ref name="XD" /> provided evidence that a strong cation-pi interaction occurs between the cation of '''nicotine''' and Trp149 in the '''neuronal-type''' receptor. The crystal structure of a molluscan acetylcholine-binding protein confirms the existence of a cation-pi interaction between the homologous Trp (Trp143) and the nicotine cation. The lower affinity of nicotine for the muscle-type, compared to the neuronal type receptors, is accounted for by differences in cation-pi interaction strength and the absence of a nicotine-receptor hydrogen bond in the former<ref name="XD" />. | ||
===Examples from Gallivan and Dougherty<ref name='GD' />=== | ===Examples from Gallivan and Dougherty<ref name='GD' />=== | ||