Design and synthesis of novel sigma receptor ligands through scaffold minimization and their application towards targeted drug delivery

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Linkens, Kathryn Taylor

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Sigma receptors are a class of proteins in which both subtypes (sigma 1 and sigma 2) have been implicated in the pathology of most central nervous system disorders and various lines of cancer. A series of norbenzomorphan compounds were recently discovered to bind sigma receptors with tunable subtype selectivity depending on the substitution pattern. To further probe the structure-activity relationship of this new class of sigma ligands, a collection of isoindoline, tetrahydroisoquinoline, and benzazepine derivatives were prepared. This new set of compounds showed affinity for sigma receptors, and have been useful tools in refining the pharmacophore model of the binding sites. Additionally, these novel sigma receptor ligands were applied towards a ligand-targeted cancer therapeutic. By chemically conjugating an anticancer agent to a ligand that will selectively target cancer cells, the therapeutic index of the drug will be improved. Herein, a sigma receptor ligand has been chemically conjugated to the chemotherapeutic, gemcitabine, and is undergoing cellular uptake and cytotoxicity tests



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