Date of Award

Spring 5-18-2012

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 available N-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).

Rights

The University of New Orleans and its agents retain the non-exclusive license to archive and make accessible this dissertation or thesis in whole or in part in all forms of media, now or hereafter known. The author retains all other ownership rights to the copyright of the thesis or dissertation.

Creative Commons License

Creative Commons Attribution 3.0 License
This work is licensed under a Creative Commons Attribution 3.0 License.

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