Date of Award
1-1-2015
Document Type
Dissertation
Degree Name
Ph.D. in Pharmaceutical Sciences
Department
Biomolecular Sciences
First Advisor
Christopher R. McCurdy
Second Advisor
Bonnie A. Avery
Third Advisor
David A. Colby
Relational Format
dissertation/thesis
Abstract
Sigma receptors are a well-defined unique class of receptors and are highly expressed in the central nervous system and also widely distributed in peripheral organs and tissues. There are two subtypes of sigma receptors: sigma-1 and sigma-2. These receptors are thought to be associated with functions and disorders such as inflammation, depression, anxiety, Alzheimer’s disease, epilepsy and drug abuse. The sigma-1 receptor has been demonstrated to be involved in acute and chronic effects of cocaine and methamphetamine toxicities. However, the role of sigma-2 receptors is less clear due to the lack of availability of detailed protein structural information and truly selective sigma-2 ligands, which hindered the pharmacological characterization of the sigma-2 subtype. In fact, the sigma-2 receptor has not yet been cloned. Several reports indicated that the activation of sigma-2 receptor also induces growth arrest and cell death in various tumor cell lines. This gives sigma-2 ligands possible application as effective agents for the treatment of cancer. In this regard, searching for selective, high affinity sigma-2 ligands led to the design and synthesis a series of isothiocyanate compounds derived from a selective sigma-2 compounds developed in our laboratory as selective irreversible sigma-2 ligands. Also, in the search for an effective drug for the treatment of cocaine abuse and addiction, and based on our previous work on CM699 that shoits ability to attenuate the cocaine self-administration. We have found that stimulant self-administration (cocaine or methamphetamine) was blocked by dual inhibition of the DAT and sigma-receptors However, CM699 had short half lives in Human and Rat liver microsomes assays (in vitro), and in rat in vivo assay. Although CM699 had a half-life of 4.4 hr in rat, a compound with utility as a treatment for stimulant abuse will need a longer half-life, achieved either by structural change or by formulation. In this regard, we have made more analogs of CM699 in order to enhance blockade of cocaine self-administration and metabolic stability. Additionally, in an effort to continue to develop highly selective sigma ligands, we have synthesized a novel series of benzofuran-based ligands, and more analogs of the highly selective sigma-1, CM304.
Recommended Citation
Alsharif, Walid, "Design, synthesis, and biological evaluation of sigma receptors (σRS) ligands as potential pharmacotherapy for cancer and drug addiction" (2015). Electronic Theses and Dissertations. 1454.
https://egrove.olemiss.edu/etd/1454
Concentration/Emphasis
Emphasis: Medicinal Chemistry