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Use of calculated cation-pi binding energies to predict relative strengths of nicotinic acetylcholine receptor agonists.

Abstract：

:Agonists and antagonists of the nicotinic acetylcholine receptor (nAChR) are used to treat nicotine addiction, neuromuscular disorders, and neurological diseases. In designing small molecule therapeutics with the nAChR as a target, it is useful to identify chemical parameters that correlate with ability to activate the receptor. Previous studies have shown that cation-pi interactions at the transmitter binding sites of the nAChR are important for receptor activation by strong agonists such as acetylcholine. We hypothesized that a calculated estimate of cation-pi binding ability could be used to predict the efficiency for channel opening (i.e., the gating efficiency) associated with activation of the acetylcholine receptor by a series of structurally related organic cations. We demonstrate that the calculated cation-pi energy is strongly correlated with gating efficiency but only weakly correlated with closed-state binding affinity. Our results suggest that cation-pi interactions contribute significantly to the open-state affinity of these cations and that the calculated cation-pi energy will be a useful parameter for designing nAChR agonists and antagonists.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Tantama M,Licht S

doi

10.1021/cb800189y

subject

Has Abstract

pub_date

2008-11-21 00:00:00

pages

693-702

issue

11

eissn

1554-8929

issn

1554-8937

pii

10.1021/cb800189y

journal_volume

3

pub_type

杂志文章

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