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

Bruce Bowler, Christopher S. Esslinger, Keith Parker, Richard J. Bridges

Keywords

AMPA, Bioisosteres, Isoxazoles, L-Glutamate

Abstract

Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system (CNS). Concentrations of L-glutamate in the CNS are regulated by a family of excitatory amino acid transporters (EAATs) that rapidly sequester and concentrate glutamate in glia and neurons, and thereby influence transmitter access to EAA receptors. In contrast to the EAAT-mediated uptake of L-Glu, the system Xc- (SXc-) transporter (an obligate exchanger of L-glutamate and L-cystine) has been implicated in the export of L-Glu from CNS cells in such a manner that it can access and activate EAA receptors. The significance of SXc- actions is reflected in the range of CNS processes including: drug addiction, brain tumor growth and oxidative protection. Recent work has focused on the synthesis of analogs and bioisosteres of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), including lipophilic analogs using lateral metalation and electrophilic quenching and their evaluations at the system xc- transporter. Bioisosteres which are not limited to amino acids were synthesized from a common intermediate. During the synthesis of hydrazone bioisosteres, most electron rich hydrazines undergo ring closer to form fused bicyclic systems, the isoxazolo[3,4-d]pyridazinones. Several hydrazone acids synthesized, bind to the SXc- with affinities comparable to those of the endogenous substrates. In contrast, the isoxazolo [3,4-d]pyridazinone analogs exhibit little or no binding. These novel isoxazole-based analogues are used in combination with SAR data from other structurally diverse inhibitors to begin constructing a pharmacophore model of the SXc- substrate binding site.

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