Abstract
Background and Purpose GABAA-α5 subunit-containing
receptors have been shown to play a key modulatory role in cognition and
represent a promising drug target for cognitive dysfunction, as well as
other disorders. We describe the preclinical and clinical profile of
basmisanil, a potent and highly selective negative allosteric modulator
(NAM) of GABAA α5 receptors. Experimental Approach In
vitro assays assessed binding and functional selectivity. In vivo
occupancy studies measured target engagement. Effects on cognition were
tested in rats (Morris water maze) and non-human primates (NHP; object
retrieval) and potential side effects (anxiety and proconvulsant) were
tested in rats. In healthy volunteers, target engagement and modulation
of neuronal network activity were assessed using PET and EEG. Key
Results Basmisanil bound to recombinant human GABAA-α5
receptors with 5 nM affinity and more than 90-fold selectivity versus
α1, α2, and α3 subunit-containing receptors. Basmisanil inhibited
GABA-induced currents at GABAA-α5 yet had little or no
effect at the other receptor subtypes. In vivo, basmisanil demonstrated
dose-dependent target engagement in rats. Basmisanil attenuated
diazepam-induced spatial learning impairment in rats and improved
executive function in NHPs. At these efficacious plasma concentrations,
basmisanil had no anxiogenic and proconvulsant effects. In healthy
volunteers, PET showed target engagement and established the plasma
exposure to receptor occupancy relationship. Basmisanil modulated brain
function reflected in characteristic changes of EEG spectral power.
There were no serious adverse events. Conclusion and Implications
Basmisanil is a highly potent and selective
GABAA α5 receptor NAM with good safety
and tolerability allowing for clinical testing in multiple brain
disorders.