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The GABAA Receptor

γ-aminobutyric acid (GABA) is one of the most important inhibitory neurotransmitters in the central nervous system. It is responsible for around 40% of all inhibitory synaptic processing. Much of GABA’s effect arises from its interaction with the fast-acting GABAA receptor. These receptors are ligand-gated chloride ion channels comprised of five protein subunits arranged in a 2:2:1 ratio. However, not all GABAA receptors are alike.

Scientists have discovered that the body produces many different protein subunits that it can incorporate into a GABAA receptor. As a result, GABAA receptors are comprised of numerous subtypes, each with a unique combination of protein subunits. Because certain subtypes are concentrated in specific regions of the CNS, each subtype produces a unique pharmacological effect when activated. Therefore, drugs that selectively target specific GABAA receptor subtypes have the potential to not only treat diseases with fewer side effects than the non-selective drugs on the market today, but they could also address new diseases.

diagram of gabaa receptor

History of GABAA Receptor and Risk of Abuse

Because the GABAA receptor is largely responsible for effects of alcohol, it can be argued that it is one of the oldest drug targets known.

In the 1870s, chloral hydrate, whose metabolite modulates the GABA receptor complex, was widely used as a sedative and as a treatment for insomnia. Although effective, abuse and dependence were major issues and by the 1920s, its use had been almost entirely supplanted by the barbiturates which work on the GABAA receptor. Unfortunately, it soon became apparent that barbiturates also carry the risk of abuse, dependence, severe withdrawal symptoms, and lethal overdose.

Although still used in some situations, the barbiturates were replaced by benzodiazepines with the advent of Librium in 1960. By the late 1970s, benzodiazepines were the most commonly prescribed drugs in the world.

New Drug Candidates with Fewer Side Effects

Recent research has shown it’s possible to design drug candidates that modulate specific GABAA receptor subtypes resulting in compounds that are efficacious yet have fewer side effects than classical non-selective drugs. Without substantial side effects, these drug candidates can then be safely administered at a higher dose, allowing for selective molecules to treat disorders that have not yet been addressed with standard GABAA modulators.

Young Boy with Golden Retriever in Meadow on Sunny Day

Novel Treatments for Itch, Pain, and Epilepsy

Originally, compounds that selectively targeted α2/α3 GABAA receptor subtypes were envisioned as being a sedation-free treatment for generalized anxiety disorders due to the overwhelming commercial success of non-selective drugs such as Xanax and Valium. However, commercial development of these drugs has dwindled over the past 10-15 years due to normal program attrition and strategic shifts in the pharmaceutical industry as companies redirected their efforts from neuroscience programs toward neurodegenerative disorders such as Alzheimer’s disease.

While α2/α3 selective compounds may still hold promise for treating anxiety-related disorders, ongoing research has revealed that these compounds may be better suited for treating other important indications such as chronic pain and certain epilepsies. One of the most recent and exciting developments is that α2/α3 selective GABAA PAMs show groundbreaking preclinical efficacy in relieving itch, and especially itch related to dermatitis.