Year of Publication
Peter A. Crooks
This project utilized synthesis and in vitro assays to generate antagonist SARs at various nAChR subtypes. Alkylation of the pyridino nitrogen of the nicotine molecule afforded subtype specific antagonists at a42* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. Using this data, a series of mono-azaaromatic quaternary salts were produced and evaluated in binding and functional assays for a42* and a7* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. Additionally, bis-azaaromatic quaternary salts were synthesized and evaluated in the same assays. Two potent lead compounds were identified. N-n-dodecylnicotinium iodide (NDDNI) was found to be very potent at both a42* nAChR subtypes and nAChR subtypes that mediate nicotine-evoked dopamine release. And the most promising candidate was N-N-bisdodecylpicolinium dibromide (bDDPiB), which was selective for the nAChR subtypes that mediate nicotine-evoked dopamine release (IC50 = 9 nM). Additionally, using the data from the SARs, predictive computer models were generated to assist in future compound assessment without in vitro assays. Three self-organizing map (SOMs) models were generated from three different sets of compounds. The groups consisted of the mono-substituted compounds, the bissubstituted compounds, and both sets combined. The models were able to successfully "bin" the test set of compounds after developing a model from a similar set of training compounds. Additionally, using genetic functional activity (GFA) algorithms an evolutionary approach to generating predictive model equations was applied to the compounds. Three separate equations were generated in order to form a predictive method for evaluating affinities at the a4b2* receptor subtype. In addition to the modeling and SAR work of the quaternary ammonium compounds, novel synthetic methods were also employed to develop enantiomerically pure nicotine analogs. Efficient enantioselective syntheses of (S)- and R-(+)-nornicotine, (S)-and R-(+)-anabasine, and (S)-and R-(+)-anatabine have been developed, affording isomers in high enantiomeric excess.
Ayers, Joshua Thomas Longen, "SYNTHESIS AND EVALUATION OF PYRIDINIUM DERIVATIVES AS CENTRAL NERVOUS SYSTEM NICOTINIC ACETYLCHOLINE RECEPTOR LIGANDS" (2006). University of Kentucky Doctoral Dissertations. 414.