The aim of the present project is the development and characterization of compound libraries that target the newly described modulatory a+/b- site in GABA_A receptors. GABA_A 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 GABA_A receptor subtypes with different localization and function thus exist. The majority of these receptors consist of two a, two b, and an additional subunit, often g or d. 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 a and b subunits of GABA_A 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 a and g2 subunits) such as the fact that alpha subtypes can be targeted selectively via this pocket, which is important to reduce unwanted side effects. In terms of differences, ligands of the new site act independently from the g2 subunit. This leads to a targeting of different receptor pools compared to the g2 dependent benzodiazepine site ligands. Together, these properties of the a+/b- 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 Down Syndrome.

In this collaborative effort we will generate and investigate novel compounds that interact with this site, understand 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.