Ligands for the GABAA receptor alpha+ / beta- interface

The brain, which is the most complex mammalian organ, maintains a delicate balance between “inhibition” and “excitation” in order to perform its many functions such as thinking, feeling and sleeping. In case of dysfunction, exact diagnosis is desirable, and should be followed by effective therapy low in side effects. Brain dysfunction is accessible to a limited degree to imaging methods, and therapy with psychopharmacological agents, such as hypnotics (sleeping aids) is possible. For many dysfunctions exact diagnostic methods are lacking, and therapy is also often not satisfactory – thus, there is great medical need for further research along the lines of diagnostic and therapeutic agents.

The project goal here was the development and testing of substance libraries which act at a recently described (modulatory alpha+/ beta-) binding site of GABAA (gamma- aminobutyric acid type A) receptors. They are the site of action for a wide range of clinically relevant agents such as benzodiazepines and barbiturates, and target of many sleeping aids, anxiolytics and sedative narcotics. They also play an important role in PET based brain imaging.

These GABA gated chloride channels are composed of five subunits which come from different subunit classes. In turn, many GABAA receptor subtypes exist that display different localization and function. The majority of these receptors contain two alpha and two beta subunits, and one additional subunit that is often gamma or delta. Drugs and ligands targeting these receptors can either alter the chloride channel, or even directly gate it from different allosteric binding sites.

In the course of the previous FWF project P 1965-B11 we described a novel binding site at the interface between alpha and beta subunits. In this project (P 27746-B27) we concentrated on improving ligands for these sites. With the accomplished improvements, chiefly in potency and selectivity, medical applications for diagnosis or therapy in insomnia, anxiety disorders, epilepsy – possibly even pain, Down syndrome, addiction or schizophrenia – move closer by several years on the long road of drug development.