Allosteric modulators of extrasynaptic delta-GABAA receptors for the treatment of postpartum depression

Postpartum depression (PPD), which is a more severe version of the common "baby blues", occurs in 15-20% of mothers and is associated with symptoms such as depressed mood, anxiety and feelings of worthlessness. Although the cause is unknown, it is hypothesised that PPD is triggered by the reduction after birth in the amount of a chemical called allopregnanolone which is well-known to have an effect on brain function and mood. This hypothesis was recently confirmed when an allopregnanolone-supplement strategy was shown to be effective in alleviating the symptoms of depression and was approved by the US Food and Drug Adminstration for the treatment of mothers with PPD. However, the drug, which is called Brexanolone (but is simply a proprietary form of allopregnanolone), has a number of significant issues associated with its use, not least of which are the need for a 60-hour intravenous infusion, serious side effects and a very high cost. As a result, Brexanolone has limited availability to the wider PPD patient population.

Brexanolone works by altering the function of a group of proteins in the brain called the GABAA receptors (GABAARs). Evidence suggests that one type of these proteins, the so-called extrasynaptic GABAARs are responsible for the beneficial effects of Brexanolone in the treatment of PPD whereas other other subtypes of GABAAR proteins are responsible for the side effects. In this proposal we aim to identify chemicals that alter the function of the extrasynaptic GABAAR proteins but do not affect those proteins responsible for the side-effects. As the next step in advancing such compounds towards the clinic and the PPD patient population, we will also demonstrate that these chemicals selectively alter the function of the extrasynaptic GABAAR proteins in intact mouse and rat brain tissue. If this project is successful and we then achieve our ultimate long-term goal of identifying a drug for treating PPD, then we believe that it could provide a step-change in the treatment of postpartum depression. As such, this present proposal represents an important first step in the process of making a significant impact within the field of maternal mental health.

Postpartum depression (PPD) is an extreme version of the "baby blues" and occurs in 15-20% of mothers within a year of giving birth. It is associated with symptoms such as depression, anxiety, and feelings of worthlessness. The recent FDA approval of Brexanolone (allopregnanolone) supports the hypothesis that PPD is caused by a reduction in the endogenous neurosteroid allopregnanolone. However, the serious side-effects, cost, and the need for a 60-h i.v. infusion are significant barriers to Brexanolone's impact within the PPD patient population.

Circulating allopregnanolone readily enters the CNS where it is a non-selective positive allosteric modulator (PAM) of various subtypes of the Y-aminobutyric acid type A receptor (GABAAR). Evidence suggests that the beneficial effects of allopregnanolone in PPD may be mediated by extrasynaptic a4Bd-GABAARs whereas the serious side-effects (sedation and unconsciousness) are caused by effects at synaptic GABAARs. Hence, a PAM that is selective for extrasynaptic d-containing GABAARs (d-GABAARs) should be efficacious in PPD, but devoid of the side-effects of allopregnanolone.

The literature delta-selective compound 2 (DS2) is a valuable tool for in vitro but not in vivo studies due to its low CNS penetration. We have synthesised and tested 300 compounds based on DS2 and have identified structurally novel d-GABAAR-selective PAMs, an exemplar of which also has good in vivo pharmacokinetics and excellent brain penetration in rats. The aim of this proposal is to combine all the desired features (i.e., selectivity, potency, membrane permeability, pharmacokinetics and brain penetration) into the same molecule(s) which can then be used to demonstrate an ex vivo and in vivo Proof-of-Mechanism for d-GABAAR-selective PAMs. Our ultimate target will be an orally bioavailable, first-in-class drug with a much-reduced cost and increased convenience relative to allopregnanolone, thereby providing significant benefit for patients with PPD.