Date of Award
Spring 5-2012
Degree Type
Dissertation
Degree Name
Ph.D.
Degree Program
Chemistry
Department
Chemistry
Major Professor
Mark Trudell
Second Advisor
Guijun Wang
Third Advisor
David Mobley
Fourth Advisor
Branco Jursic
Abstract
A series of rigid azetidenyl-based methamphetamine analogs were synthesized from commercially availableN-Boc-azetidinone. The benzylideneazetidine analogs were prepared via a Wittig olefination via the ylides generated from the corresponding triphenylphosphonium benzylhalide salts. The substituted benzylazetidine analogs were synthesized from the corresponding benzylideneazetidienes via hydrogention over palladium and platinum catalysts. The benzylideneazetidine and benzyliazetidine analogs were evaluated at monoamine transporters as a part of preliminary structure-activity study for the development of novel monoamine transporter ligands. The binding affinities of the azetidine analogs were determined at dopamine (DAT) and serotonin (SERT) transporters in rat brain tissue preparations. The preliminary in vitro binding studies revealed that the rigid scaffold of the azetidine ring system was an effective substitution for the 2-aminopropyl group of methamphetamine and led to compounds with nanomolar binding affinity at dopamine and serotonin. In general, the benzylideneazetidine analogs were more potent than the corresponding benzylazetidine analogs. In addition, the azetidine analogs were more selective for the serotonin transporter than the dopamine transporter. The 3-(3,4-dichlorobenzylidene)azetidine (24m) was the most potent analog of the series with Ki values of 139 nM for SERT and 531 nM for DAT (DAT/SERT = 3.8).
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Recommended Citation
Forsyth, Andrea N., "Synthesis and Biological Evaluation of Rigid Analogues of Methamphetamines" (2012).University of New Orleans Theses and Dissertations. 1436.
https://scholarworks.uno.edu/td/1436
Rights
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