γ-aminobutyric acid (GABA) an important inhibitory neurotransmitter in the mammalian CNS and 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 modulators with fewer side effects by fine-tuning their selectivity profile. The improved side-effect profile enables higher dose levels of drug to safely be administered. This enables these selective molecules to treat disorders not addressable with standard GABAA modulators like the classical benzodiazeopines, because they are not tolerated at the efficacious dose levels.
Our lead program selectively targets specific combinations of subunit combinations of the GABAA receptors. These molecules will be initially developed to treat dermatitis and pruritus. However, we also expect that they will be useful for a variety of other indications such as psychiatric indications, chronic pain, and certain forms of epilepsy.