CX-516

Ampakines, positive allosteric modulators of AMPA-glutamate receptors (AMPAR), have therapeutic implications in neuropsychiatric and neurological disorders in which AMPAR signaling is compromised such as Alzheimer's, ADHD, and schizophrenia. Low impact ampakines are a distinct subset of ampakines that only partially offset receptor desensitization and do not meaningfully alter binding affinity of AMPAR agonists, which may explain their lack of seizurogenic effects seen with other AMPAR positive modulators. Herein, we describe the preclinical pharmacology and antipsychotic activity of the low impact ampakine 1-(benzofurazan-5-ylcarbonyl)piperidine (CX691). CX691 moderately offsets desensitization in hippocampal patches, supporting its designation as a low impact ampakine and penetrates the blood-brain barrier. CX691 is more potent than well characterized high impact ampakines CX614 and CX546 and low impact ampakine CX516 in abrogating amphetamine-stimulated locomotor activity in Sprague Dawley rats. Low-dose CX691 synergistically reduces methamphetamine-induced locomotor activity when paired with approved antipsychotics clozapine and olanzapine. In rats treated chronically with amphetamine, CX691 retains antipsychotic activity whereas high doses of CX516 lack therapeutic effects. In contrast to haloperidol, CX691 is devoid of cataleptic activity at supratherapeutic doses in rats. CX691 enhances performance in the eight-arm radial maze, a spatial task that assesses hippocampal function, an activity of potential value for ameliorating cognitive deficits in schizophrenia. Taken together, these findings illustrate that low impact ampakines with improved potency might be useful therapeutic interventions in schizophrenic patients when given alone or as adjuncts to ongoing traditional antipsychotic drug therapies.