Preclinical Pharmacology of CX1837, a High-Impact Ampakine with an Improved Safety Margin: Implications for Treating Alzheimer's Disease and Ischemic Stroke.

Abstract

Introduction: For over a decade, AMPA receptor allosteric potentiators (AMPAkines) have shown significant effectiveness in multiple preclinical studies related to neurodegenerative and psychiatric disorders underpinned by deficient excitatory synaptic activity. Despite promising preclinical evidence, the clinical translation of AMPAkines has been slow due to the propensity of some of these compounds to produce seizures at or around therapeutic doses. Materials and: Methods: The preclinical activity of the AMPAkine CX1837 is disclosed in the current work.

Results: CX1837 enhanced synaptic transmission in hippocampal slices in vitro and dose-dependently enhanced long-term potentiation, which is believed to control memory consolidation. CX1837 boosted performance in cognition tests, such as the novel object recognition test and the win-shift radial arm maze. CX1837 also increased attentional functioning in the 5-choice serial reaction time task involving rats. CX1837 produced positive preclinical effects at 0.01-1.0 mg/kg dose and elicited epileptic effects at 10 mg/kg dose.

Discussion: CX1837 has demonstrated to have one of the largest safety margins to date in preclinical studies. Low doses of CX1837, which produce acute increases in cognition, may potentially increase neurotrophins when given chronically. This could slow the progression of Alzheimer's disease and reverse deficits secondary to ischemic stroke.

Conclusion: Together, our findings highlight CX1837 as a potential candidate for clinical development in order to treat multiple neurodegenerative and psychiatric disorders.