PUBLICATION HIGHLIGHT

Methaqualone research offers new insights for designing safer GABA(A) receptor drug targets

This publication highlight is part of the SBGrid/Meharry Medical College Communities Project, focused on science education and demonstrating how structural biology and preclinical science connect to medicine.

Methaqualone, sold under the brand name Quaalude, is a sedative-hypnotic medication. Originally methaqualone was used to treat insomnia and act as a muscle relaxer. It works by enhancing the activity of the GABA(A) receptors in the brain. GABA(A) receptors are a type of receptor that respond to the neurotransmitter gamma-aminobutyric acid, or GABA. When GABA binds to GABA(A) receptors, it results in a calming effect that reduces anxiety and promotes relaxation and sleep. Activation of GABA(A) receptors is essential for preventing overexcitation in the brain, which can lead to neurological disorders such as seizures, insomnia, and anxiety disorders.

Methaqualone was originally marketed as a safer alternative to barbiturates, another class of sedative-hypnotic medications that activates GABA(A) receptors, because it causes fewer side effects in patients. However, methaqualone soon became a commonly abused drug and led to severe addictions. The rampant increase of abuse along with the increased risk for drug overdose caused many countries to ban methaqualone, including the United States, thus leading to its classification as a controlled substance.

Methaqualone’s ban led to it, and its derivatives, becoming understudied in terms of how it activates GABA(A) receptors. Learning how methaqualone works could lead to the development of similar drugs with less potential for abuse and overdose. SBGrid member Ryan Hibbs and colleagues set out to determine how methaqualone affects GABA(A) receptors in their recent publication, Structural insights into GABA(A) receptor potentiation by Quaalude. The researchers used cryo-electron microscopy to reveal the exact binding sites and structural changes in the GABA(A) receptor when it interacts with methaqualone and a more potent derivative called 2-phenyl-3-(p-tolyl)-quinazolin-4(3H)-one, or PPTQ. They found that both drugs bind deep within the receptor, similar to other anesthetics, causing important changes that help open the receptor’s channel. Opening GABA(A) channels causes negatively charged chloride ions to flow into the neurons. The influx of chloride ions causes neurons to become hyperpolarized, meaning the neurons now carry a more negative charge and are less likely to generate an action potential, which inhibits neuron firing. Inhibition of neuron firing is what stops the brain from becoming over excited and helps us relax. Overexcitation in the brain can lead to anxiety disorders and sleep problems along with many other neurological disorders. This research provides a blueprint for designing new drugs with reduced abuse potential while maintaining their sedative and anti-seizure effects.

Read more in Nature Communications.

By KeAndreya Morrison, Meharry Medical College

KeAndreya Morrison is a biomedical sciences Ph.D. Candidate at Meharry Medical College studying the relationship between host and pathogen through the lens of structural biology. KeAndreya is a Georgia native where she completed her bachelor’s degree in biology at Fort Valley State University in Fort Valley, GA.