Year of Award

2010

Document Type

Thesis - Campus Access Only

Degree Type

Master of Science (MS)

Degree Name

Pharmaceutical Sciences

Department or School/College

Department of Biomedical and Pharmaceutical Sciences

Committee Chair

Nicholas R. Natale

Commitee Members

Christopher S. Esslinger, J. B. Alexander Ross, Keith Parker, Richard J. Bridges

Keywords

L-Glutamate, Metabotropic Glutamate Receptor, Ionotropic Glutamate Receptor, Isoxazoles

Abstract

Ligands targeting the glutamate binding proteins, both the glutamate receptors and transporters hold a great potential as medicinal agents for a wide variety of neurological disorders. In an attempt to synthesize these ligands, a number of synthetic routes have been explored. Many important intermediates have been synthesized and reaction conditions optimized. Isoxazole containing glutamate analogs have played a very important role in delineating the selectivity among glutamate binding proteins in the central nervous system (CNS). The binding studies on some of the previously synthesized isoxazole analogs indicate that there exists a distinct structure activity relationship (SAR) distinguishing the glutamate receptors and transporters which relates to the size and distance of the lipophilic group in the C-5 position from the functionalized isoxazole. This important observation has led us to examine the synthetic routes for C-3 carboxy analogs of ibotenate, homo-ibotenate, and homo-AMPA. The central aim of the project focuses on the synthesis of these C-3 carboxy analogs starting from the key intermediate ethyl-4-acetyl-5-methylisoxazole-3-carboxylate (3). Once synthesized, these analogs could be very useful in delineating the selectivity among glutamate binding proteins and can provide a wealth of information regarding their mechanism of action.

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