GABAB receptor negative allosteric modulators: A novel approach to developing non-monoaminergic antidepressants

Major depressive disorder (depression) has a huge personal, family and societal impact since it affects around 5% of the global adult population. The potentially devastating effects of depression highlight the clear need for antidepressant drugs that differ from those currently on the market. Hence, not only do around one-third of depressed individuals not respond to existing medications, but those that do may have only a limited response which can take several weeks to manifest itself. Moreover, existing drugs, which primarily aim to alter the levels of a class of brain chemicals called monoamines, can be accompanied by significant side effects including, for example, loss of sexual function and suicidal ideation. A different brain chemical, called gamma-aminobutyric acid (GABA), has for a long time been implicated in the altered brain neurochemistry that underlies depression. Based upon our understanding of how GABA alters mood, it is proposed that drugs which block the effects of GABA at a brain protein called the GABA Type B (GABAB) receptor, should have antidepressant effects. The traditional way of blocking the effects of GABA at the GABAB receptor is to use a type of drug called an antagonist which "turns off" the GABAB receptor and therefore acts like an on-off switch. For a variety of reasons, GABAB receptor antagonists do not make good drugs for human use and therefore none are currently available for use as antidepressants. In this proposal, we aim to use a much more subtle way of regulating the effects of GABA at the GABAB receptor and are aiming to identify a class of drug called a negative allosteric modulator (NAM), which acts like a dimmer switch and "turns down" (rather than antagonists which "turn off") GABAB receptor activity. These types of drugs are generally easier to develop and are much safer and/or better tolerated than drugs that turn the receptor on or off. However, it is surprising that given the underpinning scientific rationale, there have to date been no systematic attempts to identify GABAB receptor "dimmer switch" type drugs. In this proposal, we aim to conduct hit optimisation studies to improve our initial GABAB NAM screening hit series to the point where we can conduct ex vivo Proof-of-Mechanism studies in a slice electrophysiology assay. More specifically, we intend to evaluate whether a high-quality (i.e., potent, selective and cell permeable) GABAB receptor NAM can attenuate a GABAB receptor-mediated electrophysiological response.