Electronic Theses and Dissertations


Design, Synthesis, Biological Evaluation and Metabolic Stability Studies of Sigma Receptor Ligands


Rohit Bhat

Date of Award


Document Type


Degree Name

Ph.D. in Pharmaceutical Sciences

First Advisor

Christopher R. Mccurdy

Second Advisor

Samir A. Ross

Third Advisor

John S. Williamson


Sigma receptors represent a unique family of proteins that includes two subtypes: sigma-1 and sigma-2. Sigma-1 receptors have been implicated in the behavioral and motivational effects of psychostimulants as well as in the pathophysiology of depression and Alzheimer's disease. Sigma-2 receptors are widely expressed on many tumor cells and they are believed to play an important role in tumor cell proliferation. Therefore, sigma receptors are attractive targets for developing pharmaceutical agents directed to the treatment of psychostimulant abuse, cancer, Alzheimer's disease as well as diagnostic agents for cancer and brain imaging. A derivatized 2(3H)-benzothiazolone, (3-(2-(azepan-1-yl)ethyl)-6-propylbenzo[ d]thiazol-2(3H)-one) was reported to have high affinity (0.56 nM) and selectivity (over 1000 fold) for sigma-1 receptors over sigma-2 receptors. A fluorinated derivative CM304, was synthesized in our laboratory and was found to have high affinity (0.0025 nM) for sigma-1 receptors and high selectivity (> 100,000 fold) over sigma-2 receptors. Both the compounds have a benzo[d]thiazol-2(3H)one scaffold and several other structural similarities. This prompted us to investigate the structure-activity-relationship (SAR) of 3,6-disubstituted benzo[ d]thiazole-2(3H)one for affinity and selectivity at sigma receptors. A library of benzo[d]thiazol-2( 3H)one analogues were synthesized and their receptor binding affinities were evaluated in rat liver membranes using a 96 well format high throughput methodology. An additional goal of this project was to conduct microsomal stability studies on some promising sigma receptor analogues. The data gathered from the pharmacokinetic studies has provided valuable information towards the mechanism of biotransformation of this class of sigma ligands. This knowledge is helpful in designing future sigma ligands with better druggable and therapeutic profiles.



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