title: Molecular properties of local anesthetics as predictors of affinity for nicotinic acetylcholine receptors.
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.
authors.affiliation: Department of Molecular Medicine, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Oné R
authors.initials: OR
authors.lastname: Pagán
authors.forename: Kannan
authors.initials: K
authors.lastname: Sivaprakasam
authors.forename: Robert E
authors.initials: RE
authors.lastname: Oswald
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002038:Bungarotoxins / Q000493:pharmacokinetics; D002462:Cell Membrane / Q000187:drug effects; D004557:Electric Organ / Q000166:cytology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics; D010622:Phencyclidine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D011237:Predictive Value of Tests; D011487:Protein Conformation / Q000187:drug effects; D011978:Receptors, Nicotinic / Q000737:chemistry* / Q000378:metabolism*; D014101:Torpedo; D014316:Tritium / Q000493:pharmacokinetics
chemical_list: D000779:Anesthetics, Local; D002038:Bungarotoxins; D018696:Neuroprotective Agents; D011978:Receptors, Nicotinic; D014316:Tritium; C012058:tenocyclidine; D010622:Phencyclidine