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Preclinical Pharmacology of the Low-Impact Ampakine CX717

Authors :
Daniel P. Radin
Sheng Zhong
Rok Cerne
Jodi L. Smith
Jeffrey M. Witkin
Arnold Lippa
Source :
Future Pharmacology, Vol 4, Iss 3, Pp 494-509 (2024)
Publication Year :
2024
Publisher :
MDPI AG, 2024.

Abstract

Ampakines are a class of orally available positive allosteric modulators of the AMPA-glutamate receptor (AMPAR) and have therapeutic implications for neurological/neuropsychiatric disorders in which AMPAR signaling is compromised. Low-impact ampakines are a distinct subclass of drugs that only modestly offset receptor desensitization and do not alter agonist binding affinity and thus lack the neurotoxicity and epileptogenic effects associated with other AMPAR modulators. In these studies, we describe the pre-clinical pharmacology of ampakine 1-(benzofurazan-5-ylcarbonyl)morpholine (CX717). CX717 modestly offsets desensitization in hippocampal patches and augments synaptic transmission in vivo. CX717 also enhances long-term potentiation in rats, which is crucial for learning and memory. CX717 enhances performance in the eight-arm radial maze and abrogates amphetamine-induced locomotor activity while being devoid of cataleptic activity in rats. CX717 also ameliorates alfentanil-induced respiratory depression in rats and is not toxic to cultured rat neurons. CX717 is active at doses of 0.3–10 mg/kg and lacked serious adverse events in safety studies in mice up to 2000 mg/kg. CX717 was also previously shown to be safe in humans and effective in reversing opiate-induced respiratory depression and hyperactivity and inattentiveness in adults with ADHD. These findings support the continued clinical investigation of CX717 in the treatment of ADHD, dementia, and opiate-induced respiratory depression.

Details

Language :
English
ISSN :
26739879
Volume :
4
Issue :
3
Database :
Directory of Open Access Journals
Journal :
Future Pharmacology
Publication Type :
Academic Journal
Accession number :
edsdoj.64ab3660dce846598b9b47f1d4571137
Document Type :
article
Full Text :
https://doi.org/10.3390/futurepharmacol4030028