COMPOUNDS AS GABA RECEPTOR MODULATORS

COMPOUNDS AS GABA RECEPTOR MODULATORS

Researchers at UCSF have developed novel GABA-modulating pharmaceutical compounds that are potential therapeutics for the treatment of chronic pain.

Neurotransmitters are the building blocks of information transfer in the central nervous system and can modulate action potentials at the synapses of neurons by binding to their cognate receptors. Neurotransmitters generally fall into two classes. Excitatory neurotransmitters potentiate or promote action potentials, while inhibitory neurotransmitters inhibit action potentials. GABA, an inhibitory neurotransmitter, is responsible for fast inhibition in the basal ganglia by binding to y-Aminobutyric acid type A receptors (GABA_AR). GABA_ARs are ligand-gated ion channels that form as pentameric assemblies of subunits. Given their vast impact on inhibitory neurotransmission, many drugs have been designed to bind at allosteric sites on the GABA_AR to modulate ion channel opening efficacy as either positive allosteric agonists, such as benzodiazepines, or as negative allosteric antagonists. As chronic pain remains a major healthcare challenge, there is an unmet medical need for additional GABA_AR modulating compounds.

Stage of Research

The inventors have characterized a number of novel compounds that modulate the inhibitory neurotransmitter GABA. These compounds were derived from large candidate drug screen in zebrafish, a common model system for drug testing. The inventors used a library with 12,000 compounds that they then administered to zebrafish. They then evaluated the zebrafish for species-specific pain reflexes. Through this experiment, the inventors were able to narrow their candidates down to just 28 candidate compounds. These compounds were then evaluated and found to be dissolvable in pharmacologically favorable solvents.

Applications