Basmisanil, a highly selective GABAA-α5 negative allosteric modulator: preclinical pharmacology and demonstration of functional target engagement in man
| Autor: | Andreas Rothfuss, Michael Derks, Robert A. Comley, Stephane Nave, Theresa M. Ballard, Sian Lennon-Chrimes, Henner Knust, Christoph Wandel, Joerg F. Hipp, Darren Bentley, Andrew Thomas, Eric Prinssen, Gerhard Trube, Tanya L. Wallace, Jana Nöldeke, Michael Honer, Frédéric Knoflach, Maria-Clemencia Hernandez, Rodolfo Gasser, Lisa Squassante |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Allosteric modulator Science Allosteric regulation Morris water navigation task Basmisanil Article Rats Sprague-Dawley 03 medical and health sciences Radioligand Assay Xenopus laevis 0302 clinical medicine Medical research Allosteric Regulation Medicine Animals Humans Learning GABA-A Receptor Agonists Receptor Multidisciplinary GABAA receptor business.industry Drug discovery Brain Human brain Receptors GABA-A Healthy Volunteers Rats Macaca fascicularis 030104 developmental biology medicine.anatomical_structure HEK293 Cells Anxiogenic Positron-Emission Tomography Female business Neuroscience 030217 neurology & neurosurgery Biomarkers |
| Zdroj: | Scientific Reports, Vol 11, Iss 1, Pp 1-20 (2021) Scientific Reports |
| ISSN: | 2045-2322 |
| Popis: | 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. Here we report on the preclinical and early clinical profile of a novel GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, which progressed into Phase II trials for intellectual disability in Down syndrome and cognitive impairment associated with schizophrenia. Preclinical pharmacology studies showed that basmisanil is the most selective GABAA-α5 receptor NAM described so far. 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. Moreover, basmisanil inhibited GABA-induced currents at GABAA-α5 yet had little or no effect at the other receptor subtypes. An in vivo occupancy study in rats showed dose-dependent target engagement and was utilized to establish the plasma exposure to receptor occupancy relationship. At estimated receptor occupancies between 30 and 65% basmisanil attenuated diazepam-induced spatial learning impairment in rats (Morris water maze), improved executive function in non-human primates (object retrieval), without showing anxiogenic or proconvulsant effects in rats. During the Phase I open-label studies, basmisanil showed good safety and tolerability in healthy volunteers at maximum GABAA-α5 receptor occupancy as confirmed by PET analysis with the tracer [11C]-Ro 15-4513. An exploratory EEG study provided evidence for functional activity of basmisanil in human brain. Therefore, these preclinical and early clinical studies show that basmisanil has an ideal profile to investigate potential clinical benefits of GABAA-α5 receptor negative modulation. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|