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Preclinical and Clinical Pharmacology of Basmisanil, a Novel Selective GABAA-α5 Receptor Negative Allosteric Modulator
  • +16
  • Joerg Hipp,
  • Frédéric Knoflach,
  • Robert Comley,
  • Theresa Ballard,
  • Michael Honer,
  • Gerhard Trube,
  • Rodolfo Gasser,
  • Eric P. Prinssen,
  • Tanya Wallace,
  • Andreas Rothfuss,
  • Henner Knust,
  • Sian Lennon-Chrimes,
  • Michael Derks,
  • Lisa Squassante,
  • Stephane Nave,
  • Jana Noeldeke,
  • Christoph Wandel,
  • Andrew Thomas,
  • Maria-Clemencia Hernandez
Joerg Hipp
F Hoffmann-La Roche AG Research and Development Division
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Frédéric Knoflach
F Hoffmann-La Roche AG Research and Development Division
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Robert Comley
F Hoffmann-La Roche AG Research and Development Division
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Theresa Ballard
F Hoffmann-La Roche AG Research and Development Division
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Michael Honer
F Hoffmann-La Roche AG Research and Development Division
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Gerhard Trube
F Hoffmann-La Roche AG Research and Development Division
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Rodolfo Gasser
F Hoffmann-La Roche AG Research and Development Division
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Eric P. Prinssen
F Hoffmann-La Roche AG Research and Development Division
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Tanya Wallace
F Hoffmann-La Roche AG Research and Development Division
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Andreas Rothfuss
F Hoffmann-La Roche AG Research and Development Division
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Henner Knust
F Hoffmann-La Roche AG Research and Development Division
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Sian Lennon-Chrimes
F Hoffmann-La Roche AG Research and Development Division
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Michael Derks
F Hoffmann-La Roche AG Research and Development Division
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Lisa Squassante
F Hoffmann-La Roche AG Research and Development Division
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Stephane Nave
F Hoffmann-La Roche AG Research and Development Division
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Jana Noeldeke
F Hoffmann-La Roche AG Research and Development Division
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Christoph Wandel
F Hoffmann-La Roche AG Research and Development Division
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Andrew Thomas
F Hoffmann-La Roche AG Research and Development Division
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Maria-Clemencia Hernandez
F Hoffmann-La Roche AG Research and Development Division
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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.