GABAA receptors are ligand gated chloride conducting ion channels belonging to the cys-loop family. The receptors are made up of five subunits (termed α1-6, β1-3, γ1-3, δ, ε, θ and π) which form a central pore through which ions pass when the channel is activated by the neurotransmitter GABA. Various combinations of the subunits exist in the body presenting a myriad of different receptors with different pharmacology. A number of known pharmaceuticals such as benzodiazepines and volatile anaesthetics exert their effects via modulation of GABAA receptors but are generally non- or poorly selective for the specific subtypes. Benzodiazepines exhibit quite poor selectivity with respect to the identity of the GABAA α subunit, modulating receptors made up of combinations of α1, α2, α3 or α5 with β and γ2. As receptors with each specific subunit combination have specific roles in the CNS, compounds with improved selectivity would be expected to retain some of the (desired) pharmacological properties of benzodiazepines without the other (unwanted) properties. The α1 subunit containing receptors have been associated with the sedation, ataxia and abuse potential of benzodiazepines, and therefore a selective compound that modulates only α2 and α3 containing receptors might not be expected to possess these undesired properties.
GABA mediated spinal inhibition is a natural mechanism occurring in the spinal cord that controls (or “gates”) the flow of painful and non-painful stimuli to the brain. Scientific evidence indicates that chronic pain states are associated with a loss of this inhibitory function (often referred to as “dis-inhibition”) and therefore restoring or enhancing the impaired GABAA signalling with a positive modulator could re-balance the excitatory and inhibitory events in the spinal cord after neuropathic injury. GABAA α2 and α3 containing receptors are present in the spinal cord and recent research has highlighted selective positive modulation of these receptors as a novel approach for the treatment of neuropathic pain.
The program is in preclinical development.