Ph.D. (Doctor of Philosophy)
Department of Biological Sciences
Local anesthetics; Molecular biology; Pharmacology
Bupivacaine is among the most widely used local anesthetics (LAs) for invasive procedures and postoperative pain relief because of its long duration of action and considerable potency. Bupivacaine carries a risk for cardiotoxicity and the relationship between its structure and its anesthetic action is incompletely known. This study was designed to characterize how changes in the aromatic ring of a class of carbamoyl piperidines (CPs), which structurally resemble bupivacaine, alter anesthetic action. In most of the CPs, the carbonyl carbon is directly bonded to the piperidine nitrogen (called the 1N position) and the piperidine nitrogen lacks substitution; bupivacaine, in contrast, features a 2N motif. The major objective was to determine how the placement and number of methyl group substitutions on the aromatic rings of the CPs alters potency and reversibility of anesthetic block. Armed with this information, structural changes in bupivacaine or CPs could be suggested to design a new and safer LA.||The blocking action of the CPs was investigated using a modified single-sucrose gap technique for recording action potentials from frog and rat nerve. To assay whether CPs preferentially block open sodium channels, CP blocking experiments were conducted on nerves pretreated with an alpha-scorpion toxin. The slopes of the dose-response relationships of the CPs varied and were greater than one and consistent with the hypothesis that some CPs may bind to more than one site on sodium channels. The potency of the CPs with two methyl substituents on the aromatic ring is maximized when the methyl groups are separated by two positions. Potent CPs tend to result in smaller recoveries from block once the CPs are removed from the nerve. Phasic blocking potency increases as hydrophobicity increases. The CPs did not preferentially block open Na channels, as some LAs do. There was no significant difference in tonic blocking potencies of the CPs when applied to frog or rat nerves, suggesting that their action might be similar in humans. Among the 1N CPs, the half maximal blocking dose is predicted as a function of pKa, molar volume, and methyl group positions. However, the half maximal blocking dose for the 2N CPs depends only on pKa. These CPs might present less risk for toxicity than bupivacaine.
Hussain, Rob, "Novel uncharged local anesthetics" (2014). Graduate Research Theses & Dissertations. 4143.
Northern Illinois University
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