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Dissertation - University Access Only
Doctor of Philosophy (PhD)
Corticotropin releasing factor (CRF) is a neuropeptide hormone produced from the hypothalamus that coordinates behavioral, endocrine and autonomic functions in stress response and its dysregulation has been implicated in stress disorders, depression, anxiety, irritable bowel disorder, alcohol and addictive drug withdrawal symptoms. New drugs that can target the CRF function may represent a new development of neuropsychiatric medicines to treat various stress-related disorders. Several classes of small molecule non-peptide CRF receptor antagonists have been developed and, in this study, two series of new pyrimidines and thiazolo[4,5-d]pyrimidines were designed based on the structural features of the basic pharmacophore and prominent CRF antagonists. A total of 79 compounds were synthesized including all intermediates and final target compounds. A multi-step synthesis was used to prepare each group of the target compounds. The detailed synthesis of all compounds is described and the structures of all the synthesized compounds are characterized and confirmed by spectral data including 1H NMR, 13C-NMR, mass spectroscopy and also micro-elemental analysis for all the final compounds. The 50 final target compounds were screened for their binding affinity to CRF1 receptors on two stages. The first stage was screening the compounds for their ability to inhibit the [125I]Tyr0-Savaugine binding to the CRF1 receptors in HEK 293 cells at 500- 1000 nM concentration. Based on initial screening studies, in the second stage, derivatives that showed 50% or more inhibition were selected for competition binding studies to further determine their IC50 values. Comparison with Antalarmin, a potent CRF1 antagonist, were also carried out in competition binding study. None of the 22 substituted thiazolo[4,5-d]pyrimdines showed 50% or more inhibition at 1000 nM, and thus were not considered for the second evaluation protocol. On the other hand, four new pyrimidines showed 50% or more inhibition of binding of [125I]Tyr0-Savaugine to the CRF1 receptors and thus passed on to the second protocol. These four compounds showed -log IC50 values of 6.61-6.27 compared to -log IC50 value of 7.73 for Antalarmin used as a standard CRF1 receptor antagonist. It was concluded that further structural modifications of these four lead compounds may lead to compounds with superior CRF1 antagonist activity and a potential for development as new antidepressant and anti-anxiety agents.
Library of Congress Subject Headings
Corticotropin releasing hormone
Includes bibliographical references (pages 154-178)
Number of Pages
South Dakota State University
In Copyright - Non-Commercial Use Permitted
Kuppast, Bhimanna, "Synthesis and Biological Evaluation of Substituted Thiazolo(4,5-d)Pyrimidines and Substituted Pyrimidines as Corticotropin Releasing Factor (CRF) Receptor Antagonists" (2014). Electronic Theses and Dissertations. 1567.