Molecular properties of local anesthetics as predictors of affinity for nicotinic acetylcholine receptors.

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TitleMolecular properties of local anesthetics as predictors of affinity for nicotinic acetylcholine receptors.
Publication TypeJournal Article
Year of Publication2007
AuthorsPagán, OR, Sivaprakasam, K, Oswald, RE
JournalJ Neurosci Res
Volume85
Issue13
Pagination2943-9
Date Published2007 Oct
ISSN0360-4012
KeywordsAnesthetics, Local, Animals, Binding, Competitive, Bungarotoxins, Cell Membrane, Electric Organ, Neuroprotective Agents, Phencyclidine, Predictive Value of Tests, Protein Conformation, Receptors, Nicotinic, Torpedo, Tritium
Abstract

In spinal anesthesia, the effects of local anesthetics (LAs) are not completely explained by sodium channel inhibition. Other targets include neuronal nicotinic acetylcholine receptors (nAChRs). LA affinities for the Torpedo californica nAChR were measured by inhibition of [(3)H]TCP binding and correlated with molecular volume, surface area, molecular weight, and log of the octanol-water partition coefficients (P and D). To understand the molecular determinants important for interaction with the nAChR, ester and amide LAs were compared separately. Also, correlations with the aromatic/linker half and the hydrophilic half of the LA molecules were considered individually. The IC(50)s of the ester LAs correlated better with the molecular volume, surface area, molecular weight, and log P of the aromatic/linker half of the molecules; whereas the IC(50)s for amide LAs correlated better with the four parameters based on the hydrophilic half. These correlations were used to predict the IC(50) of various LAs (including several not studied here) and to compare these values with the published values. The predicted values of IC(50) correlated well with the published results both for neuronal and for electroplaque-desensitized nAChR, suggesting that the results can be generalized to include neuronal nAChRs.

DOI10.1002/jnr.21402
Alternate JournalJ. Neurosci. Res.
PubMed ID17600837
Grant List5F34GM020771 / GM / NIGMS NIH HHS / United States
5R01DA011643 / DA / NIDA NIH HHS / United States