Browsing by Subject "Mixture-based positional scanning"

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    Discovery of Peptide and Peptidomimetic Based Ligands Targeting the Melanocortin Receptors: A campaign in mixture-based positional scanning, chemical topology, and structure-activity relationships
    (2016-07) Doering, Skye
    Despite aggressive public health initiatives over the last few decades, the proportion of the population who are obese and overweight continues to expand at an alarming rate. A multitude of external factors, such as easily accessible high-calorie foods and an overall lack of physical activity, are contributing to this epidemic; however, the basic regulatory pathways within the body are not completely understood. Evidence suggests many of the signaling systems regulating energy homeostasis feed into the brain and the final step is mediated by the melanocortin receptors. It has been demonstrated that melanocortin agonists decrease food intake whereas melanocortin antagonists increase food intake when administrated centrally (Nature, 1997, 165-8). Out of the two centrally expressed receptors, it has been hypothesized the melanocortin-4 receptor (MC4R) effects immediate satiety whereas the melanocortin-3 receptor (MC3R) effects the long-term energy needs and food consumption in the body. In order to test this hypothesis there is a need for melanocortin-3 receptor selective compounds which currently do not exist. The work reported within this dissertation lead to the discovery of new dual MC3R agonist/MC4R antagonist ligands in addition to MC3R antagonist ligands selective for the MC3R over the MC4R. These novel ligands were based on new tetrapeptide templates which were identified via mixture-based positional scanning and classic structure-activity relationship studies. This work was supported by NIH grant R01DK091906.