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AMPA‐type glutamate receptors (AMPARs) mediate the majority of fast excitatory synaptic transmission in the mammalian brain. Ampakines, positive allosteric modulators of AMPAR, hold significant potential for the treatment of a wide range of neurological/neuropsychiatric disorders in which excitatory synaptic transmission is compromised. Low‐impact ampakines are a distinct subset of ampakines that accelerate channel opening yet minimally affect receptor desensitization, which may explain their lack of seizurogenic effects at therapeutic doses in preclinical models. CX1739 is a low‐impact ampakine that has shown efficacy in preclinical studies. The current clinical study examined the tolerability and pharmacokinetics of CX1739 in healthy male volunteers in a 2‐part study. Part A was a single dose escalation study (100‐1200 mg, 48 patients) and Part B was a multiple dose ascending study (300‐600 mg BID for 7‐10 days, 32 patients). CX1739 was well tolerated up to 900 mg once daily (QD) and 450 mg twice a day, with the prominent side effects being headache and nausea. Importantly, the half‐life of CX1739 was 6‐9 hours, and Tmax was 1‐5 hours. CX1739 Cmax and AUC were dose‐proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) has reached epidemic proportions worldwide. The consequences of TBI can be severe even with repetitive mild trauma. If death and coma are avoided, the consequences of TBI in the long term typically involve dizziness, sleep disturbances, headache, seizures, cognitive impairment, focal deficits, depression, and anxiety. The severity of brain injury is a significant predictor of outcome. However, the heterogenous nature of the injury makes prognosis difficult. The present review of the literature focuses on the genetics of TBI including genome wide (GWAS) data and candidate gene associations, among them brain-derived neurotrophic factor (BDNF) with TBI and development of post-traumatic epilepsy (PTE). Molecular biomarkers of TBI are also discussed with a focus on proteins and the inflammatory protein IL1-β. The secondary medical sequela to TBI of cognitive impairment, PTE, headache and risk for neurodegenerative disorders is also discussed. This overview of TBI concludes with a review and discussion of the medical management of TBI and the medicines used for and being developed at the preclinical and clinical stages for the treatment of TBI and its host of life-debilitating symptoms. [ABSTRACT FROM AUTHOR]

Ampakines—positive allosteric modulators of AMPA-type glutamate receptors (AMPARs)—are drug candidates that have shown substantial promise in pre-clinical models of various neurodegenerative and neuropsychiatric diseases. Much of the study of ampakines has focused on how these drugs modulate neuronal AMPARs to achieve certain therapeutic effects. However, astrocytes also express functional AMPARs and their physiology may be sensitive to modulation by ampakines. Herein, we investigate the effects of multiple ampakines on calcium levels in cortical astrocytes. We find that ampakines augment cytosolic calcium elevations in astrocytes to an extent far greater than that achieved by AMPA alone. This effect is amenable to competitive AMPAR blockade. Furthermore, calcium induction is sensitive to phospholipase Cβ antagonism and blockade of inositol triphosphate receptors located on the endoplasmic reticulum. Low-impact ampakines exerted weaker effects on cytosolic calcium levels in astrocytes and higher concentrations were required to observe an effect. Furthermore, high doses of the low-impact ampakine, CX717, were not toxic to cortical astrocytes at high concentrations, which may serve to differentiate low-impact ampakines from classical AMPAR positive modulators like cyclothiazide. As ampakines are further developed for clinical use, it would be prudent to determine the extent to and manner by which they affect astrocytes, as these effects may also underpin their therapeutic utility in CNS pathologies. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

α‐Amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) positive allosteric modulators (AMPAkines) have a multitude of promising therapeutic properties. The pharmaceutical development of high impact AMPAkines has, however, been limited by the appearance of calcium‐dependent neuronal toxicity and convulsions in vivo. Such toxicity is not observed at exceptionally high concentrations of low impact AMPAkines. Because most AMPAR are somewhat impermeable to calcium, the current study sought to examine the extent to which different mechanisms contribute to the rise in intracellular calcium in the presence of high impact ampakines. In the presence of AMPA alone, cytosolic calcium elevation is shown to be sodium‐dependent. In the presence of high impact AMPAkines such as cyclothiazide (CTZ) or CX614, however, AMPAR potentiation also activates an additional mechanism that induces calcium release from endoplasmic reticular (ER) stores. The pathway that connects AMPAR to the ER system involves a Gq‐protein, phospholipase Cβ‐mediated inositol triphosphate (InsP3) formation, and ultimately stimulation of InsP3‐receptors located on the ER. 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. [ABSTRACT FROM AUTHOR]

NMDA receptor antagonists have potential for therapeutics in neurological and psychiatric diseases, including neurodegenerative diseases, epilepsy, traumatic brain injury, substance abuse disorder (SUD), and major depressive disorder (MDD). (S)-ketamine was the first of a novel class of antidepressants, rapid-acting antidepressants, to be approved for medical use. The stereoisomer, (R)-ketamine (arketamine), is currently under development for treatment-resistant depression (TRD). The compound has demonstrated efficacy in multiple animal models. Two clinical studies disclosed efficacy in TRD and bipolar depression. A study by the drug sponsor recently failed to reach a priori clinical endpoints but post hoc analysis revealed efficacy. The clinical value of (R)-ketamine is supported by experimental data in humans and rodents, showing that it is less sedating, does not produce marked psychotomimetic or dissociative effects, has less abuse potential than (S)-ketamine, and produces efficacy in animal models of a range of neurological and psychiatric disorders. The mechanisms of action of the antidepressant effects of (R)-ketamine are hypothesized to be due to NMDA receptor antagonism and/or non-NMDA receptor mechanisms. We suggest that further clinical experimentation with (R)-ketamine will create novel and improved medicines for some of the neurological and psychiatric disorders that are underserved by current medications. [ABSTRACT FROM AUTHOR]

AMPA-glutamate receptors (AMPARs) are expressed throughout the CNS and mediate the majority of fast excitatory synaptic transmission. Ampakines are orally available small molecules that bind allosterically to AMPARs and enhance excitatory currents elicited by the endogenous agonist glutamate. In preclinical studies, ampakines are effective in ameliorating symptoms in a battery of neurodegenerative and neuropsychiatric diseases in which excitatory transmission is compromised. However, the development of ampakines as medicines was slowed by the emergence of neurotoxicity and seizures in rodents due to some ampakines. Here, we describe the preclinical pharmacology of a novel ampakine, N-methyl-N-(tetrahydro-2H-pyran-4-yl)benzo[c][1,2,5] oxadiazole-5-carboxamide (CX1739), that does not induce seizures in animals or humans at efficacious doses. CX1739 dose-dependently enhanced long-term potentiation in vivo in rats, a process thought to be a molecular substrate of learning and memory. Correspondingly, CX1739 dose-dependently enhanced performance in assays that probed multiple aspects of cognition—the novel object recognition test, the win shift radial arm maze, and the five-choice serial reaction time task in rats. CX1739 also abrogated amphetamine-induced locomotor activity, demonstrating that it may be given in conjunction with stimulants for pro-cognitive gains while mitigating the side effects of stimulant-based ADHD medications. CX1739 also rapidly reversed opioid-induced respiratory depression. While efficacy in these tests occurred at doses of 0.03–18 mg/kg, there were no adverse events detected in safety studies in rats up to 2000 mg/kg. These preclinical findings suggest that CX1739 can be translated safely into the clinical setting to potentially treat dementia, neuropsychiatric disorders, and the life-threatening complication of opiate-induced suppression of endogenous inspiratory breathing rhythms. [ABSTRACT FROM AUTHOR]