Year of Award

2011

Document Type

Professional Paper - Campus Access Only

Degree Type

Master of Interdisciplinary Studies (MIS)

Degree Name

Interdisciplinary Studies

Other Degree Name/Area of Focus

Medicinal Chemistry

Department or School/College

Interdisciplinary Studies Program

Committee Chair

Nicholas Natale

Commitee Members

J.B. Alexander Ross, Charles Thompson, John Gerdes

Keywords

Glutamate, Isoxazole, MARS, Transporter, Xc-

Abstract

The purpose of this study was the synthesis of selective ligands that are important to understand the classes of glutamate binding proteins (i.e. Glu receptors vs. transporters) and also to define their mechanism of action. Increased selectivity at the various Glu binding proteins should result in better therapeutic outcomes to a host of neurological disorders of the Central Nervous System (CNS). Glutamate, a major excitatory amino acid in the CNS, works through four different classes of receptors; three that are heterogeneous, ionotropic excitatory amino acid (EAA) receptors (iGluRs), named N-methyl –D- aspartic acid (NMDA). (RS)-2-amino-3-(3-hydroxy-5-methylisoxazole-4-yl) propionic acid (AMPA), and kainic acid (KA) receptors, and the fourth heterogeneous class is the metabotropic EAA receptor (mGluRs). It is now generally agreed that iGluRs as well as subtypes of these receptors are potential targets for therapeutic intervention in a number of diseases and that iGluRs and mGluRs have important roles in the healthy as well as diseased CNS. Thus, ligands that bind these receptors with a high degree of affinity may serve as molecular probes into the mechanism of action of these receptors. 2-Amino-(3-carboxyl-5-methyl-4-isoxazoleyl) propionic acid (ACPA) has been identified as a promising lead in the search for potential selective glutamate binding protein ligands due to its high efficacy and specificity. In previous work from our group, it was found that isoxazole analogs bearing a hydrozone moiety in the ACPA class had promising Xc_ activity, however, the synthesis was plagued by the observation of ring closure to the isoxazolo[3,4-d]pyridazinones, which had lowered biological activity. A mechanistic hypothesis is advanced in which a carbonyl group is inserted into the structure to slow or prevent cyclization to the less active [3,4-d] by-product. This study discusses a comparison between the Microwave Accelerated Reaction System (MARS) and conventional reflux methods to prepare the desired hydrozone-containing targets. MARS proved to produce isoxazoles with the open hydrazone form predominating, constituting a complete SAR series, and exhibited robust activity in biological assays.

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© Copyright 2011 Afnan Lilly Matti