Doctoral Dissertations
Date of Award
8-1996
Degree Type
Dissertation
Degree Name
Doctor of Philosophy
Major
Chemistry
Major Professor
George W. Kabalka
Abstract
The dopaminergic system within the brain has been implicated in the etiology of a number of diseases, including schizophrenia and Parkinson's disease. A series of thienyl analogs of spiperone was synthesized for testing as D2 receptor imaging agents. The 5'-iodo analog was tested in vivo, with generally poor results, despite its high in vitro activity. The [18F]-N-fluoroethyl analog was shown to be an excellent imaging agent, with good specificity and uptake. A series of cocaine analogs, the 3-phenylcarbamoyl ecgonines, was also synthesized as potential dopamine reuptake transporter (DAT) inhibitors. Various functional groups were incorporated at the C2 ester, the phenyl group of the carbamate, and the N8 nitrogen. Conformational analysis by NMR and computational techniques have established likely three-dimensional structures for the compounds, and an attempt to correlate structural features with in vitro testing results has been made. in vitro testing of the lead compound, 3-(3'-nitrophenyl)carbamoyl ecgonine methyl ester, revealed it to be potent (Ki = 264 nm) but unselective (Ki 5-HTT/Ki DAT = 1.5). The most potent compound synthesized was the 3-(3'-nitrophenyl) carbamoyl ecgonine cyclopropylmethyl ester (Ki = 727 nm), which also has much improved specificity (Ki 5-HTT/Ki DAT ≥ 13.75). The 3-(3'-nitrophenyl) carbamoyl-8-cyanomethyl-ecgonine methyl ester was found to have good potency (Ki = 23.6 nm) and the best selectivity known (Ki DAT/Ki 5-HTT = 208) for the serotonin transporter.
Recommended Citation
Gotsick, James Timothy, "Synthesis, characterization, and computational analysis of a series of butyrothiophenones and 3-carbamoyl ecgonines. " PhD diss., University of Tennessee, 1996.
https://trace.tennessee.edu/utk_graddiss/9746