Year of Award
2022
Document Type
Dissertation
Degree Type
Doctor of Philosophy (PhD)
Degree Name
Medicinal Chemistry
Department or School/College
Department of Biomedical and Pharmaceutical Sciences
Committee Chair
Nicholas Natale
Commitee Members
Christopher Palmer, Keith Parker, Elizabeth Putnam, Monica Serban
Keywords
Drug development, Isoxazoles, Metabotropic glutamate receptors
Publisher
University of Montana
Abstract
The seven transmembrane (7TM) superfamily, also known as G-protein coupled receptors (GPCR), are one of the largest superfamilies in the human genome. With approximately 30% of marketed drugs targeting the GPCRs, these proteins are among the most successful as therapeutic targets. Within the GPCR receptor family there is a subgroup called the metabotropic glutamate receptors (mGluR). Compounds that target mGluRs are important for the treatment of a variety of central nervous system (CNS) disorders, as well as cancer. The mGluR2 subtype is a target for treatment of anxiety and schizophrenia. Activation of mGluR4 helps to ease the symptoms of Parkinson’s disease and may even slow progress of the disease. Additionally, both of these receptors have been implicated in the treatment of variety of cancers such as giloma, medulloblastoma, or colorectal carcinoma, presenting another target to overcome these diseases. Selectively targeting the mGluRs are difficult due to the high sequence similarities. This difficulty can be overcome by targeting the allosteric site, which is located in the 7TM.Our isoxazolo[3,4-d]pyridazinones compounds were tested and found to have selective activity at mGluR 2 and 4. This selectivity, along with other tests, imply binding may not be at the venus flytrap domain (where glutamate binds), but rather at the allosteric site as positive allosteric modulators (PAMs). Further modifications of our compounds will be developed to optimize selectivity and activity, based on structural drug design and modeling at the allosteric site.
Recommended Citation
Gates, Christina Ann, "Development of the novel isoxazolo[3,4-d]pyridazinone scaffold, which positively modulates the metabotropic glutamate receptor subtypes 2 and 4" (2022). Graduate Student Theses, Dissertations, & Professional Papers. 11830.
https://scholarworks.umt.edu/etd/11830
© Copyright 2022 Christina Ann Gates