Behavioural pharmacology of the α5-GABAA receptor antagonist S44819: Enhancement and remediation of cognitive performance in preclinical models

• Published in: Neuropharmacology Vol. 125; pp. 30 - 38
• Main Authors: Gacsályi, István, Móricz, Krisztina, Gigler, Gábor, Wellmann, János, Nagy, Katalin, Ling, István, Barkóczy, József, Haller, József, Lambert, Jeremy J., Szénási, Gábor, Spedding, Michael, Antoni, Ferenc A.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.10.2017
• Subjects: Alpha5-GABAA antagonists; Behavioural pharmacology; Cognitive performance; GABAA receptors; S44819; Cognitive performance; S44819; Alpha5-GABAA antagonists; Behavioural pharmacology; GABAA receptors
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2017.07.005

Previous work has shown that S44819 is a novel GABAA receptor (GABAAR) antagonist, which is selective for extrasynaptic GABAARs incorporating the α5 subunit (α5-GABAARs). The present study reports on the preclinical neuropsychopharmacological profile of S44819. Significantly, no sedative or pro-convulsive side effects of S44819 were found at doses up to 30 mg/kg i.p. Object recognition (OR) memory in intact mice was enhanced by S44819 (0.3 mg/kg p.o.) given before the acquisition trial. Mice treated with phencyclidine for two weeks and tested six days after the cessation of treatment failed to show OR memory. This deficit was corrected by a single administration of S44819 (0.1, 0.3 or 1 mg/kg p.o.) prior to the acquisition trial. The amnestic effect of ketamine in rats tested in the eight-arm radial maze (reference and working memory versions) was blocked by S44819 (3 mg/kg p.o.). Extinction of cued fear was preserved during treatment with S44819 (3 mg/kg/diem i.p.). Administration of S44819 had no significant effect in the Vogel-conflict test, the elevated plus maze, the forced swim, the marble-burying and the tail-suspension tests. In contrast, anxiolytic/antidepressant-like effects of the compound were found in paradigms that have mnemonic components, such as social interaction, fear-potentiated startle and social avoidance induced by negative life experience. In summary, S44819 enhanced intact recognition memory and ameliorated memory deficits induced by inhibition of NMDA receptors. Anxiolytic/antidepressant efficacy was limited to paradigms involving cognitive function. In conclusion, S44819 is a novel psychoactive pro-cognitive compound with potential as a therapeutic agent in dementia. •A novel competitive inhibitor selective for extrasynaptic α5-GABAA receptors (S44819) was tested in behavioural paradigms.•The compound was effective in improving long-term as well as short-term (working) memory in mice and rats.•S44819 reversed the impairment of object recognition memory induced by sub-chronic treatment of mice with phencyclidine.•S44819 also showed significant anxiolytic/antidepressant-like activity in tests that have amnemonic component.•The compound is now in Phase 2 clinical trials.