Development of G-quadruplex stabilizers as anticancer drug therapy and selective agonists of the human oxytocin receptor as a therapeutic tool for neuropsychiatric disorders.

摘要

The principal aim of pharmacology in drug discovery is the characterization of drug activity by system-independent scales that allow prediction of drug activity in all cellular systems. This thesis concentrated in two drug targets: telomeres and GPCRs. Telomere biology is a validated anticancer drug target. G-protein-coupled receptors (GPCRs) recognize external ligands and transmit signals to cellular G-proteins (guanine-nucleotide-binding proteins) to elicit a response. These receptors are tractable for drug discovery because they are on the cell surface therefore drugs do not need to penetrate the cell to produce an effect [1]. In 2000, nearly half of all prescription drugs in the US were targeted towards GPCRs [2].;The projects in this dissertation will describe two different approaches to the successful identification of small-molecules that interact with their validated targets. The first project focused on the identification of new G-quadruplex stabilizers and their ability to inhibit human telomerase as an anticancer drug modality. The second project focused on the efforts made towards the identification of novel small-molecules that selectively activate the human oxytocin receptor to regulate complex behaviors in animal models with therapeutic implications in various neuropsychiatric disorders.