γ-aminobutyric acid (GABA) is recognized as the most important inhibitory neurotransmitter in the mammalian CNS, as it comprises 40% of inhibitory synaptic processing. Much of its action arises from its interaction with the GABAA.
GABAA Receptor History
Because GABA’s receptor GABAA 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.
GABAA Receptor Insights
Recent research has shown that it is possible to design GABAA receptor targeting with fewer side effects by fine-tuning their selectivity profile. It should further be possible to treat disorders not addressable with standard GABAA modulators like the benzodiazeopines.
Our lead program will seek compounds that selectively target GABAA receptors that contain proprietary subunit combinations not previously targeted by competitors. These molecules will be initially developed to treat neuropathic pain. However, we also expect that they will be useful for a variety of other indications.
We will also develop neurosteroids that modulate the GABAA receptor. Neurosteroids bind the GABAA receptor at a different site than benzodiazeopines. As a result, they inherently have a different selectivity profile and are typically strong activators of the receptor. In addition to the disorders indicated for our lead program, these molecules may have special utility for certain epilepsies.