Honors Theses

Date of Award

Spring 5-4-2022

Document Type

Undergraduate Thesis


School of Pharmacy

First Advisor

David Colby

Second Advisor

John Rimoldi

Third Advisor

Jing Li

Relational Format



The proper functioning of the CNS depends on the balance between excitatory and inhibitory neurotransmitters. While excitation is primarily regulated by glutamate, inhibition is regulated by γ-aminobutyric acid (GABA). When GABA binds to a GABA receptor, there is a block in nerve transmission which is important when studying pain and drug addiction. There are two types of GABA receptors that are used as drug targets: GABA-A and GABA-B. While GABA-A receptors are ionotropic and ligand-gated ion channels, GABA-B receptors are G-protein coupled receptors that are used by cells to convert extracellular signals into intracellular responses. Although many therapeutics modulate the GABA-A receptor, such as benzodiazepines like valium, only one FDA approved drug targets the GABA-B receptor. Specifically, baclofen (Lioresal®) is the pharmaceutical that acts as a selective agonist of the GABA-B receptor and is used to treat pain and spasticity in patients with multiple sclerosis and spinal cord injury. The majority of existing treatments for addiction rely on the understanding of excitatory neurotransmitters, such as dopamine and serotonin; however, studying the role of inhibitory neurotransmitters, such as GABA, is lacking. Modulation of the GABA-B receptor has the potential to lead to new interventions in the treatment of substance use disorders. Although baclofen selectively targets the GABA-B receptor, its inability to accumulate in the brain severely limits its potential in substance use disorders. To identify new classes of molecules that activate the GABA-B receptor, difluoromethyl ketones were synthesized and evaluated for their structure-activity relationships at this receptor.

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