Ampalex (CX516) / RespireRx - LARVOL DELTA

Antipsychotic-like pharmacological profile of the low impact ampakine CX691 (farampator): Implications for the use of low impact ampakines in the treatment of schizophrenia. (PubMed, J Psychiatr Res) - "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 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."

Journal • ADHD (Impulsive Aggression) • Alzheimer's Disease • Attention Deficit Hyperactivity Disorder • CNS Disorders • Cognitive Disorders • Psychiatry • Schizophrenia

High Impact AMPAkines Induce a Gq-Protein Coupled Endoplasmic Calcium Release in Cortical Neurons: A Possible Mechanism for Explaining the Toxicity of High Impact AMPAkines. (PubMed, Synapse) - "The same linkage was not observed using high concentrations of the low impact AMPAkines, CX516 (Ampalex), and CX717. We also demonstrate that CX614 produces neuronal hyper-excitability at therapeutic doses, whereas the newer generation low impact AMPAkine CX1739 is safe at exceedingly high doses. Although earlier studies have demonstrated a functional linkage between AMPAR and G-proteins, this report demonstrates that in the presence of high impact AMPAkines, AMPAR also couple to a Gq-protein, which triggers a secondary calcium release from the ER and provides insight into the disparate actions of high and low impact AMPAkines."

Journal • CNS Disorders • Epilepsy

Chronic administration of caffeine, modafinil, AVL-3288 and CX516 induces time-dependent complex effects on cognition and mood in an animal model of sleep deprivation. (PubMed, Pharmacol Biochem Behav) - "Caffeine has anxiolytic effect in acute administration. The improvement of memory in chronic period may be associated with the neuroprotective effects of caffeine. AVL-3288 had a short-term positive effect on memory, but tolerance to these effects developed over time. Furthermore, no anhedonia was observed in AVL-3288 and CX516 groups in contrast to vehicle, caffeine and modafinil groups. This indicates that AVL-3288 and CX516 may show protective effect against depression."

Journal • Preclinical • CNS Disorders • Depression • Mood Disorders • Psychiatry

Microcircuit failure in STXBP1 encephalopathy leads to hyperexcitability. (PubMed, Cell Rep Med) - "CX516, an ampakine that enhances excitatory synapses, restores interneuron recruitment and prevents hyperexcitability. These findings establish deficits in excitatory synapses in microcircuits as a key underlying mechanism for cortical hyperexcitability in a mouse model of Stxbp1 disorder and identify compounds enhancing excitation as a direction for therapy."

Journal • CNS Disorders • Developmental Disorders • Epilepsy • Psychiatry • XBP1

AMPAkines have site-specific analgesic effects in the cortex. (PubMed, Mol Pain) - "We found that direct delivery of CX516, a well-known AMPAkine, into the ACC had no effect on the aversive response to pain in rats...In contrast, AMPAkine delivery into the prelimbic region of the prefrontal cortex (PL) reduced pain aversion. These results indicate that the analgesic effects of AMPAkines in the cortex are likely mediated by the PFC but not the ACC."

Journal • Pain

Carbonylative Transformations Using a DMAP-Based Pd-Catalyst through Ex Situ CO Generation. (PubMed, J Org Chem) - "Various value-added pharmaceutically relevant compounds such as CX-516, CX-546, and farampator were synthesized using the technique. Furthermore, the commercially designed COware was engineered to COware-RB setup for sequential one-pot synthesis of indenoisoquinolines (topoisomerase I inhibitors)."

Journal

Fast Progression in Amyotrophic Lateral Sclerosis: Pathways and Biomarkers from Multi-Omics Analysis (AAN 2022) - "Recent edaravone and AMX0035 clinical trials showed treatment response in fast progressors who declined more than 1.5/month on the ALS Functional Rating Scale–revised (ALSFRS-R) scale over 6 months...Candidate drugs included amantadine, cephalexin, ampalex and mycretin. Multiple clades associated with fast progressors suggested heterogeneity among this patient population, with identified gene and protein sets providing potentially useful prognostic biomarkers for stratification and individualized treatment."

Biomarker • Amyotrophic Lateral Sclerosis • CNS Disorders • Mental Retardation

AMPAkine CX516 alleviated chronic ethanol exposure-induced neurodegeneration and depressive-like behavior in mice. (PubMed, Toxicol Appl Pharmacol) - "Furthermore, CX516 significantly diminished the inhibition of the ERK1/2-BDNF-TrkB pathway in the hippocampus of ethanol-exposed mice. In addition, CX516 attenuated the levels of pro-inflammatory (IL-6, IL-1β), apoptosis (BAX, BCL-2), and neurodegeneration (FJC) in the mouse hippocampus induced by CEE."

Journal • Preclinical • CNS Disorders • Depression • Psychiatry • BCL2 • BDNF • IL1B • IL6

AMPA receptors mediate the pro-cognitive effects of electrical and optogenetic stimulation of the medial prefrontal cortex in antidepressant non-responsive Wistar-Kyoto rats. (PubMed, J Psychopharmacol) - "Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats."

Journal • CNS Disorders • Depression • Psychiatry

Vocabulary comprehension in adults with fragile X syndrome (FXS). (PubMed, J Neurodev Disord) - "Findings from this investigation strongly suggest that the PPVT-III should not be used as a screening tool for language levels or cognitive function in clinical studies since the scores from the PPVT-III were not representative of global language or non-verbal cognitive skills in adults with intellectual disabilities. This finding is critical in order to understand how to evaluate, as well as to treat, language in individuals with FXS. Development of efficient and appropriate tools to measure language, cognition, and behavior in individuals with FXS is essential."

Clinical • Journal • Autism Spectrum Disorder • Developmental Disorders • Fragile X Syndrome • Genetic Disorders • Mental Retardation

Scn2a haploinsufficient mice display a spectrum of phenotypes affecting anxiety, sociability, memory flexibility and ampakine CX516 rescues their hyperactivity. (PubMed, Mol Autism) - "Scn2a mice exhibit a spectrum of phenotypes commonly observed in models of schizophrenia and autism spectrum disorder. Treatment with the CX516 ampakine, which ameliorates hyperactivity in these mice, could be a potential therapeutic strategy to rescue some of the disease phenotypes."

Journal • Preclinical