Preclinical characterization of a water-soluble low-impact ampakine prodrug, CX1942 and its active moiety, CX1763

<b>Aim:</b> AMPA-glutamate receptor (AMPAR) dysfunction mediates multiple neurological/neuropsychiatric disorders. Ampakines bind AMPARs and allosterically enhance glutamate-elicited currents. This report describes the activity of the water-soluble ampakine CX1942 prodrug and the active moiety CX1763. <b>Results:</b> CX1763 and CX1942 enhance synaptic transmission in hippocampi of rats. CX1763 increases attention in the 5CSRTT in rats and reduces amphetamine-induced hyperactivity in mice. CX1942 potently reverses opioid-induced respiratory depression in rats. CX1942/CX1763 was effective at 2.5–10 mg/kg. CX1763 lacked epileptogenicity up to 1500 mg/kg in rats. <b>Conclusion:</b> These data document that CX1942 and CX1763 are active and without prominent side effects in multiple pre-clinical assays. CX1942 could serve as a prodrug for CX1763 with the advantage of high water solubility as in an intravenous formulation. The water-soluble glycine ester pro-drug of CX1763, CX1942 is potent and active against alfentanil-induced respiratory depression <i>in vivo</i> CX1942 and CX1763 produce a durable increase in hippocampal EPSP <i>in vivo</i> CX1763 increases metrics of attention in rodents while reducing hyperactivity associated with amphetamine, indicating multiple potential benefits for ADHD treatment CX1763/CX1942 is therapeutically active at doses of 2.5–10 mg/kg and CX1763 lacks epileptic and fatal toxicities up to 1500 mg/kg, demonstrating a notable safety margin, justifying further preclinical and clinical explorations