Ligands for the GABAA receptor alpha+ /beta- interface

The aim of the present project is the development and characterization of compound libraries that target the newly described extracellular modulatory alpha+ /beta- binding site in GABAA receptors. GABAA receptors (gamma-amino butyric acid type A receptors) are the site of action of many clinically important drugs, such as benzodiazepines or barbiturates and the targets for sleep medications, anxiolytics, or diverse narcotics. They are the major inhibitory transmitter receptors in the brain. These GABA-gated chloride channels are composed of five subunits that can belong to different subunit classes. Multiple GABAA receptor subtypes with different localization and function thus exist. The majority of these receptors consist of two alpha and two beta subunits together with an additional fifth subunit, which often is a gamma or a delta subunit. Other receptors incorporating so-called rare subunits also exist. Drugs either modulate GABA-evoked chloride influx or directly induce channel opening via different allosteric binding sites. In the course of the FWF project P19653-B11, we identified and characterized a new binding site at the interface between alpha and beta subunits of GABAA receptors and several ligands that interact with this site and thereby change receptor response to the transmitter. This binding site shares some properties with the benzodiazepine binding site (between alpha and gamma subunits) such as the fact that alpha subtypes can be targeted selectively via this pocket. This is important to reduce unwanted side effects. In terms of different properties of the novel site, ligands binding between alpha and beta subunits act independently from the gamma subunit. This leads to a targeting of different receptor pools compared to the benzodiazepine site ligands. Together, these properties of the novel pocket make it a potentially very interesting as target for future medications that may offer novel therapeutic strategies for the treatment of many neuropsychiatric conditions, such as insomnia, anxiety disorders, epilepsy, or may even be useful in conditions such as pain, Down Syndrome, addiction or schizophrenia. In this collaborative effort we will generate and investigate novel compounds that interact with this site, study the interactions that govern the ligated states and lead to allosteric modulation, and ultimately produce compounds exhibiting higher potency and selectivity for these binding sites for a possible future therapeutic application.

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.