Physiological signature of a novel potentiator of AMPA receptor signalling

• Published in: Molecular and cellular neuroscience 2018-10, Vol.92, p.82-92
• Main Authors: Szulc, Blanka R, Hilton, Stephen T, Ruiz, Arnaud J
• Format: Article
• Language: English
• Subjects: Animals; CA3 Region, Hippocampal - drug effects; CA3 Region, Hippocampal - physiology; Glutamic Acid - metabolism; Long-Term Potentiation - drug effects; Male; Mossy Fibers, Hippocampal - drug effects; Mossy Fibers, Hippocampal - physiology; Nootropic Agents - chemistry; Nootropic Agents - pharmacology; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Rats; Rats, Sprague-Dawley; Receptors, AMPA - metabolism; Synaptic Transmission - drug effects
• ISSN: 1044-7431; 1095-9327
• DOI: 10.1016/j.mcn.2018.07.003

We have synthesized a novel small molecule based on the pyrrolidinone-containing core structure of clausenamide, which is a candidate anti-dementia drug. The synthetic route yielded multi-gram quantities of an isomeric racemate mixture in a short number of steps. When tested in hippocampal slices from young adult rats the compound enhanced AMPA receptor-mediated signalling at mossy fibre synapses, and potentiated inward currents evoked by local application of l-glutamate onto CA3 pyramidal neurons. It facilitated the induction of mossy fibre LTP, but the magnitude of potentiation was smaller than that observed in untreated slices. The racemic mixture was separated and it was shown that only the (-) enantiomer was active. Toxicity analysis indicated that cell lines tolerated the compound at concentrations well above those enhancing synaptic transmission. Our results unveil a small molecule whose physiological signature resembles that of a potent nootropic drug.