molecules of the month

The Roche GABAA-α5 selective negative allosteric modulator (NAM), basmisanil, is a Ph. II candidate for intellectual disability in Down syndrome. GABAA receptors assemble as pentamers of subunits, and non- subunit selective compounds have anxiogenic or convulsive side effects. Basimasil is the only safe and selective GABAA-α5 inhibitor that has entered clinical development. It is highly selective for the GABAA-α5 receptor subtype and is >90x selective against -α1, -α2, and -α3 subunit-containing receptors, and accordingly demonstrated good tolerability in healthy volunteers at maximum target occupancy, confirmed with a [11C]-radiolabeled PET tracer. The team reports human PET and EEG data in this paper, providing evidence for functional target engagement in the human brain for this well-tolerated compound.