L-655708 is a selective and highly potent GABAA receptor reverse agonist with a Ki value of 0.45 nM.

GABAA:0.45 nM (Ki)

L655708, a potent and selective inverse agonist, targets the benzodiazepine site of GABAA receptors that contain the α5 subunit (Ki = 0.45 nM). It exhibits remarkable selectivity, with a 50-100-fold preference for GABAA receptors containing α1, α2, α3, or α6 subunits when combined with β3 and γ2. In a mouse hippocampal slice model, L655708 enhances long-term potentiation (LTP) and improves spatial learning. Notably, it does so without displaying proconvulsant activity.

At an intraperitoneal administration of 0.7 mg/kg, L-655708 achieves 60-70% occupancy of α5 GABAA receptors, with minimal binding to GABAA receptors containing α1, α2, and α3 subunits. Furthermore, there are no significant off-target behavioral effects, such as sedation and motor impairment.