Engineering systemically bioavailable analogs of endogenous neuropeptides

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Title Engineering systemically bioavailable analogs of endogenous neuropeptides
Publication Type thesis
School or College College of Pharmacy
Department Medicinal Chemistry
Author Green, Brad Reed
Date 2010-12
Description A significant amount of effort has been put into the research and development of peptide-based drugs for the treatment of human disease. The use of anticonvulsant neuropeptides for the treatment of pain and epilepsy has recently shown promise. Neuropeptides such as galanin (Gal), neuropeptide Y (NPY), neurotensin (NT), and neuropeptide W (NPW) modulate their biological activities through their respective receptor targets in the brain. Introduced intracerebroventricularly, these compounds have been shown to reduce pain and seizure activity. Upon systemic administration, however, these compounds do not exhibit the same potency. The metabolic instability and inability to penetrate the blood-brain barrier (BBB) has precluded their widespread use as drugs for neurological disorders. This work will describe the application of the lipidizationcationization strategy to several endogenous neuropeptides towards increasing their metabolic stability and improving systemic bioavailability. Based on existing structure activity relationship (SAR) information, analogs of Gal, NPY NT, and NPW were designed and chemically synthesized. The combination of increased cationic character (oligo-Lys motifs) and increased lipophilicity (lipoamino acid) resulted in analogs with increased octanol-water partitioning coefficients (logD), significantly improved metabolic stabilities, while retaining high affinities for their native receptors. Furthermore, these analogs were shown to modulate seizure activity in animal models of epilepsy upon systemic administration. Our results suggest that the cationizationlipidization strategy may be broadly applicable across a wide variety of neuropeptides, opening up a large repertoire of new drug candidates for the treatment of neurological disorders.
Type Text
Publisher University of Utah
Subject Neurosciences; Biochemistry; Pharmacy sciences
Subject MESH Neuropeptides; Receptors, Galanin; Receptor, Galanin, Type 3; Epilepsy; Anticonvulsants; Neuralgia; Peptide Hydrolases; Biological Availability; NAX-5055
Dissertation Institution University of Utah
Dissertation Name Master of Science
Language eng
Relation is Version of Digital reproduction of Engineering Systematically Bioavailable Analogs of Endogenous Neuropeptides. Spencer S. Eccles Health Sciences Library. Print version available at J. Willard Marriott Library Special Collections.
Rights Management (c) Brad Reed Green
Format application/pdf
Format Medium application/pdf
Format Extent 46,468,347 bytes
Source Original in Marriott Library Special Collections, RM31.5 2010.G73
ARK ark:/87278/s6x385nj
Setname ir_etd
ID 196337
Reference URL https://collections.lib.utah.edu/ark:/87278/s6x385nj
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