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

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 and these symptoms are largely unresponsive to existing antidepressants such as the selective serotonin reuptake inhibitors (SSRIs), exemplified by, for example, Prozac. The FDA approvals in 2019 and 2023, respectively of Brexanolone (i.v. allopregnanolone) and the synthetic allopregnanolone analogue Zuranolone (Zurzuvae, SAGE-217) support the hypothesis that PPD is caused by a reduction in the endogenous neurosteroid allopregnanolone. However, the serious side-effects, costs ($34,000) and a 60-h i.v. infusion are significant barriers to the uptake of Brexanolone that have resulted in modest sales of only $2.0M in Q4, 2023. Similarly, Zurzuvae, had only very modest 1Q '24 revenues of $12.4M, suggesting that it's cost ($15,900) and a Black Box warning of possible "central nervous system (CNS) depressant effects" are both significant barriers to its widespread acceptance. The significant side effects of both Brexanolone and Zuranolone (neither of which are currently available in the UK) are related to their inherent lack of selectivity across different (i.e., synaptic and extrasynaptic) subtypes of ?-aminobutyric acid type A receptors (GABAARs). There therefore remains a huge unmet need for new treatments for postpartum depression. The "allopregnanolone withdrawal" hypothesis is based upon observations that plasma allopregnanolone concentrations increase markedly during pregnancy but then falls dramatically after birth. During pregnancy, the circulating allopregnanolone readily enters the CNS where it is a non-selective positive allosteric modulator (PAM) of various subtypes (synaptic and extrasynaptic) of GABAARs. Evidence suggests that in PPD the beneficial effects of Brexanolone and Zuranolone are mediated by extrasynaptic d subunit-containing-GABAARs (d-GABAARs) whereas the serious side-effects are caused by effects at synaptic (?2 subunit-containing) GABAARs. Hence, a PAM that is selective for d-GABAARs should be efficacious in PPD, but devoid of the side-effects of allopregnanolone (Brexanolone) and Zurzuvae. In the initial two-year project (MRC DPFS award MR/V038540/1), we explored two chemotypes based upon the poorly brain penetrant literature delta-selective compound 2 (DS2). The exemplar compound MDI-117289 potentiates the effects of GABA at human recombinant d-GABAARs and consistent with the mode of action, it potentiates extrasynaptic (tonic) but not synaptic (phasic) currents in a mouse brain slice electrophysiology assay. Moreover, MDI-117289 not only attenuated pentylenetetrazole-induced seizures in mice but also produced a pronounced effect on mouse brain local field potentials (an in vivo electrophysiological assay), rat brain EEG signals and reversed behavioural deficits in mice produced by early-life adversity, a well-known risk factor for PPD. These ex vivo and in vivo Proof-of-Mechanism studies were the primary endpoints of the previous proposal and therefore represent the successful conclusion of that project. In this current 2-year proposal, we aim to further optimise our lead series with respect to in vitro and in vivo (primarily pharmacokinetic) parameters, including efficacy in an animal model of postpartum depression and by the end of the 12-month Milestone 1 period select a single preclinical candidate compound. This will then be progressed into the 12-month Milestone 2 exploratory non-GLP rat and second species (mini pig or dog) toxicology studies. The overall output of this project will be a compound ready for the GLP toxicology studies required prior to the commencement of Phase 1 clinical studies.