GABAkines - Advances in the discovery, development, and commercialization of positive allosteric modulators of GABAA receptors

Abstract

Positive allosteric modulators of γ-aminobutyric acid-A (GABA_A) receptors or GABAkines have been widely used medicines for over 70 years for anxiety, epilepsy, sleep, and other disorders. Traditional GABAkines like diazepam have safety and tolerability concerns that include sedation, motor-impairment, respiratory depression, tolerance and dependence. Multiple GABAkines have entered clinical development but the issue of side-effects has not been fully solved. The compounds that are presently being developed and commercialized include several neuroactive steroids (an allopregnanolone formulation (brexanolone), an allopregnanolone prodrug (LYT-300), Sage-324, zuranolone, and ganaxolone), the α2/3-preferring GABAkine, KRM-II-81, and the α2/3/5-preferring GABAkine PF-06372865 (darigabat). The neuroactive steroids are in clinical development for post-partum depression, intractable epilepsy, tremor, status epilepticus, and genetic epilepsy disorders. Darigabat is in development for epilepsy and anxiety. The imidazodiazepine, KRM-II-81 is efficacious in animal models for the treatment of epilepsy and post-traumatic epilepsy, acute and chronic pain, as well as anxiety and depression. The efficacy of KRM-II-81 in models of pharmacoresistant epilepsy, preventing the development of seizure sensitization, and in brain tissue of intractable epileptic patients bodes well for improved therapeutics. Medicinal chemistry efforts are also ongoing to identify novel and improved GABAkines. The data document gaps in our understanding of the molecular pharmacology of GABAkines that drive differential pharmacological profiles, but emphasize advancements in the ability to successfully utilize GABA_A receptor potentiation for therapeutic gain in neurology and psychiatry.

Keywords: Anxiety; Darigabat; Depression; Epilepsy; GABAkines; KRM-II-81; Neuroactive steroids; Pain.

Figure 1.

Structures of GABA and the direct-acting GABA_A receptor agonists muscimol, gaboxadol (also known as THIP), and baclofen.

Figure 2.

An example of GABA – glutamate dynamics. A simplified postulated mechanism of action of the rapid-acting antidepressant ketamine. Glutamate binding to AMPA receptors on postsynaptic neurons results in AMPA receptor amplification, initiating a biological cascade in a host of intermediary biology pathways that are associated with the antidepressant responses to ketamine. eEF2: eukaryotic elongation factor 2; ERK: extracellular signal–regulated kinase; mTOR: mammalian target of rapamycin. From Witkin et al. (2019b) with permission of the publisher.

Figure 3.

Structures of first- and second-generation GABAkines used in the treatment of anxiety along with the currently widely prescribed drug alprazolam. Not shown here are barbiturates more prominently used as anxiolytics prior to the commercialization of the structures shown.

Figure 4.

Structures of some compounds with anxio-selective profiles that entered into clinical investigation.

Figure 5.

Structures of some early compounds developed for their reduced potentiation of GABA_A receptors containing α1 protein subunits. The structure of NS11821 has not been publicly disclosed.

Figure 6.

Chemical structures of the neuroactive steroid GABAkines in clinical development including an intravenous formulation of the endogenous steroid allopregnanolone, brexanolone (Zulresso^®), zuranolone, and ganaxolone. The structure of Sage-324 has not been disclosed. LYT-300 is an oral prodrug form of allopregnanolone whose structure has not been disclosed.

Figure 7.

Structures of the imidazodiazepine KRM-II-81 and structural analogs are shown. Also pictured is the structurally-distinct compound PF-06372865. Both KRM-II-81 (α2/3-selective) and PF-06372865 (α2/3/5-selective), also known as CVL-865, are currently in development.