Authors:

Leah Freeman

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About Paper:

y-Aminobutyric acid (GABA) is an essential inhibitory neurotransmitter in the central nervous system. Low levels of GABA have been tied to a variety of neurological diseases, including epilepsy, neuropathic pain, Alzheimer's disease, Parkinson's disease, as well as other neurodegenerative diseases. GABA aminotransferase (GABA-AT) is the primary enzyme responsible for metabolizing GABA in the brain. Inhibiting GABA-AT can increase GABA concentrations, making it a valuable therapeutic target for treating neurological disorders. CPP-115 is a GABA-AT mechanism-based inactivator that has proven relatively effective in inhibiting GABA-AT activity. The goal of this study is to introduce a hydroxy group at the 5-position of CPP-115 to explore whether this modification enhances its activity towards GABA-AT and improves selectivity over a structurally similar enzyme, Ornithine aminotransferase (OAT). Docking studies showed that a 5-hydroxy analogue exhibited stronger interactions with GABA-AT than with OAT. The synthesis of this analogue was carried out and characterized using mass spectroscopy and NMR spectroscopy. The activity of the final compound was evaluated using a biological assay that quantified its rate of inhibition of GABA-AT and OAT. The biological assay showed that the 5-hydroxy analogue had very little GABA-AT inactivation activity. Therefore, the 5-hydroxy modification decreases the affinity and selectivity of CPP-115 to GABA-AT compared to standard CPP-115, making this analogue unsuccessful in improving CPP-115. These results inform future analogue syntheses, suggesting that the addition of hydrophobic groups at the 5-position of CPP-115, or modifications at other positions, could be more effective in optimizing CPP-115.

Source:

Northwestern University

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Co-authors:

Leah Freeman