{"id":{"repo_id":"mississippi","oai_identifier":"oai:egrove.olemiss.edu:etd-2453"},"canonical_url":"https://search.dev.ndltd.org/etd/mississippi/oai:egrove.olemiss.edu:etd-2453","repository":{"repo_id":"mississippi","name":"University of Mississippi","base_url":"https://egrove.olemiss.edu/do/oai/"},"display":{"title":"Design, synthesis, and biological evaluation of sigma receptors (σRS) ligands as potential pharmacotherapy for cancer and drug addiction","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.","abstract_html":"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.","abstract_has_math":false,"creators":["Alsharif, Walid"],"institution":null,"degree_name":"Ph.D. in Pharmaceutical Sciences","degree_level":"Dissertation","degree_discipline":"Biomolecular Sciences","degree_department":null,"school":null,"contributors":["Christopher R. McCurdy","Bonnie A. Avery","David A. Colby"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2015,"date_issued":"2015-01-01T08:00:00Z","date_published":"2015-01-01T08:00:00Z","updated_at":"2026-07-24T03:06:53Z","subjects":["Medicinal Chemistry","Pharmacy and Pharmaceutical Sciences"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://egrove.olemiss.edu/etd/1454","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Christopher R. McCurdy","Bonnie A. Avery","David A. Colby"]},{"key":"dc:creator","label":"Author","values":["Alsharif, Walid"]}]},{"id":"academic_context","label":"Academic Context","entries":[{"key":"dc:date.available","label":"Dc Date Available","values":["2020-01-23T08:00:00Z"]},{"key":"thesis:degree_discipline","label":"Discipline","values":["Biomolecular Sciences"]},{"key":"thesis:degree_level","label":"Degree Level","values":["Dissertation"]},{"key":"thesis:degree_name","label":"Degree Name","values":["Ph.D. in Pharmaceutical Sciences"]}]},{"id":"subjects_keywords","label":"Subjects and Keywords","entries":[{"key":"dc:subject","label":"Dc Subject","values":["Medicinal Chemistry","Pharmacy and Pharmaceutical Sciences"]}]},{"id":"identifiers","label":"Identifiers","entries":[{"key":"dc:identifier","label":"Identifier","values":["https://egrove.olemiss.edu/etd/1454"]}]},{"id":"additional","label":"Additional Metadata","entries":[{"key":"dc:description.abstract","label":"Abstract","values":["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."]},{"key":"dc:title","label":"Title","values":["Design, synthesis, and biological evaluation of sigma receptors (σRS) ligands as potential pharmacotherapy for cancer and drug addiction"]}]}],"canonical_facts":{"dc:contributor":["Christopher R. McCurdy","Bonnie A. Avery","David A. Colby"],"dc:creator":["Alsharif, Walid"],"dc:date.available":["2020-01-23T08:00:00Z"],"dc:description.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."],"dc:identifier":["https://egrove.olemiss.edu/etd/1454"],"dc:subject":["Medicinal Chemistry","Pharmacy and Pharmaceutical Sciences"],"dc:title":["Design, synthesis, and biological evaluation of sigma receptors (σRS) ligands as potential pharmacotherapy for cancer and drug addiction"],"thesis:degree_discipline":["Biomolecular Sciences"],"thesis:degree_level":["Dissertation"],"thesis:degree_name":["Ph.D. in Pharmaceutical Sciences"]},"updated_at":"2026-07-24T03:06:53Z"}