RO4938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors

Abstract

The data further support the potential of GABAA alpha5 receptors as a target for cognition-enhancing drugs. The dual binding and functional selectivity offers an ideal profile for cognition-enhancing effects without the unwanted side effects associated with activity at other GABAA receptor subtypes.

α5GABAAReceptor Activity Sets the Threshold for Long-Term Potentiation and Constrains Hippocampus-Dependent Memory

“…The results presented here will be of potential therapeutic interest because they suggest a cellular mechanism to account for the memory-enhancing properties of inhibitors of ␣5GABA A Rs Ballard et al, 2009). Indiscriminant reduction in GABA A R-mediated inhibition by nonselective antagonists facilitates synaptic plasticity (Wigström and Gustafsson, 1983), increases vigilance (Ferraro et al, 1999), and improves memory performance (Zarrindast et al, 2002); however, these nonselective drugs have no therapeutic utility because of their proconvulsant and anxiogenic properties (Ben-Ari et al, 2007).…”

Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

“…Like other α 5 GABA A R negative modulators, the imidazo-triazolo-benzodiazepine RO4938581 managed to improve the cognitive performance of rats in the DMTP and Morris water maze models. In addition, RO4938581 enhanced the prefrontal executive function of cynomolgus monkeys in an object retrieval task without having any adverse effects on anxiety, convulsion, motor coordination or muscle strength [52,53]. RO4938581 also significantly improved the performance of scopolamine-and diazepam-induced memory-impaired rats in the DMTP and…”

“…Morris water maze, respectively [52,53]. PWZ-029 is unusual in that it inhibits α 5 GABA A Rs at nanomolar concentrations but potentiates other GABA A R isoforms at much lower potencies [54,55].…”

“…Subunit specific compounds can also be used as pharmacological probes to understand the basic neural mechanisms of the aforementioned diseases. water maze model [52,53] …”

Riluzole Does Not Affect Hippocampal Synaptic Plasticity and Spatial Memory, Which Are Impaired by Diazepam in Rats

“…Diazepam (10 mg/kg) or riluzole (3 and 10 mg/kg) was prepared as described previously (6) and administered orally 60 min prior to the training trial. The dose of diazepam was chosen based on previous experiments (15). We have previously demonstrated that 3 mg/kg but not 10 mg/kg of riluzole has anxiolytic-like effects in rats (6).…”