Synthesis, characterization, and computational analysis of a series of butyrothiophenones and 3-carbamoyl ecgonines

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 (K_i = 264 nm) but unselective (K_i 5-HTT/K_i DAT = 1.5). The most potent compound synthesized was the 3-(3'-nitrophenyl) carbamoyl ecgonine cyclopropylmethyl ester (K_i = 727 nm), which also has much improved specificity (K_i 5-HTT/K_i DAT ≥ 13.75). The 3-(3'-nitrophenyl) carbamoyl-8-cyanomethyl-ecgonine methyl ester was found to have good potency (K_i = 23.6 nm) and the best selectivity known (K_i DAT/K_i 5-HTT = 208) for the serotonin transporter.