Ampakine trials

In March , Cortex was awarded extended funding under the University of California BioSTAR projectfor the research project: 'Ampakine modulation of brain neurotrophin expression: a novel therapeutic strategy'.

Randomized, double-blind, placebo-controlled international clinical trial of the Ampakine CX in elderly participants with mild cognitive impairment: a progress report. J Mol Neurosci Aug-Oct;19 "This progress report briefly describes the rationale and study design for the first cross-national clinical study of a positive AMPA-type glutamate receptor modulator in subjects with mild cognitive impairment MCI.

Previous preclinical and pilot clinical studies have shown that CX has the ability to enhance memory and cognition. Design of the trial, including outcome measures and inclusion criteria, was aided by an international panel of experts in the newly emerging field of MCI. Enhancement by an ampakine of memory encoding in humans. Exp Neurol Aug; 2 "Acentrally active drug that enhances AMPA receptor-mediated currents was tested for its effects on memory in humans.

Evidence for a positive influence on encoding was obtained in four tests: i visual associations, ii recognition of odors, iii acquisition of a visuospatial maze, and iv location and identity of playing cards.

The drug did not improve scores in a task requiring cued recall of verbal information. The selectivity of drug effects on memory was confirmed using tests of visual recognition, motor performance, and general intellectual functioning. These results suggest that positive modulators of AMPA receptors selectively improve at least some aspects of memory. Evidence that a positive modulator of AMPA-type glutamate receptors improves delayed recall in aged humans. Exp Neurol May; 1 "Elderly subjects years were tested for recall of nonsense syllables prior to and after oral administration of 1- quinoxalin-6 ylcarbonyl piperidine CX , a centrally active drug that enhances currents mediated by AMPA-type glutamate receptors.

A significant and positive drug effect was found for delayed 5 min recall at 75 min posttreatment; average scores for the highest dose group were more than twofold greater than for the placebo group. The drug had no evident influence on heart rate or self-assessment of several psychological variables. Psychological effects of a drug that facilitates brain AMPA receptors.

Int Clin Psychopharmacol Mar;11 1 "The effects of 1- quinoxalinylcarbonyl piperidine CX , a centrally active compound that facilitates AMPA receptor-mediated synaptic responses, were tested in human subjects. Control subjects exhibited poorer performance in the second session than in the first while subjects given mg of the drug did not. There were no pre- vs post-treatment differences in immediate recall in either group.

The drug did not reliably affect self-assessment scores for any of several psychological variables but did disrupt the normally present correlations for within-subject changes in the variables.

These results suggest that AMPA receptor modulators may 1 improve memory under some circumstances and 2 produce psychological effects that are subtle or not related to specific mood states.

Facilitation of olfactory learning by a modulator of AMPA receptors. J Neurosci Dec;15 12 "The effects of a benzoyl-piperidine drug BDP that facilitates AMPA receptor-mediated synaptic responses were tested on the acquisition and retention of long-term memory at dosages that had no detectable effects on a variety of performance measures. The effects of the lower concentration were tested on two-odor discrimination learning in rats that had extensive training on the task.

Retention performance was not significantly better than chance There were no evident effects of the drug on response latencies during acquisition. These results suggest that AMPA receptor modulators reduce the amount of training needed for the formation of long-term memory and do so at dosages which have little effect on variables that secondarily influence acquisition. Possible reasons for this selectivity are discussed. Remembrance of odors past: enhancement by central facilitation of AMPA receptors.

Behav Neurosci Oct; 5 "Pharmacological facilitation of the alpha-aminohydroxymethylisoxazole AMPA -type glutamate receptor has recently been demonstrated to enhance synaptic responses, promote long-term potentiation LTP induction in freely moving rats, and facilitate learning and retention of information.

The present study verifies and extends the behavioral action of allosteric AMPA receptor modulation by showing that the benzoyl-piperidine compound BDP promotes retention of olfactory and transient spatial memory in a dose-dependent fashion; is only effective when given before but not after training, consistent with the hypothesis that glutamatergic facilitation enhances information encoding by means of action on the machinery involved in LTP induction; and, following suboptimal training in a paradigm of enduring memory, prolongs the ability of rats to retain odors by extending the decay of weak memory traces.

Modulating excitatory synaptic neurotransmission: potential treatment for neurological disease? Derangements in AMPA receptor-mediated synaptic transmission may be a contributing factor in neurological and neurodegenerative diseases and could be a target for therapeutic intervention.

For example, AMPA modulators facilitate long-term potentiation, which may be important for memory storage, and facilitate memory encoding in behavioral experiments.

Thus, AMPA modulators might ameliorate memory deficits that occur in dementia, such as Alzheimer's disease. Modulation of AMPA receptor kinetics differentially influences synaptic plasticity in the hippocampus. However, these modulators are highly diverse in their effects on receptor kinetics and synaptic transmission and thus may differ also in their efficacy to promote changes in synaptic strength.

The present study examined three of these modulators for their effects on synaptic plasticity in field CA1 of hippocampal slices, two of them being the benzamide drugs 1- quinoxalinylcarbonyl piperidine CX and 1- 1,4-benzodioxanylcarbonyl piperidine CX which prominently enhance synaptic transmission yet differ in their relative impact on amplitude versus duration of the synaptic response. The third drug was cyclothiazide which potently blocks AMPA receptor desensitization.

Effects on plasticity were assessed by measuring i the likelihood of obtaining stable potentiation when using theta-burst stimulation with three instead of four pulses per burst, ii the maximum amount of potentiation under optimal stimulation conditions, and iii the effect on long-term depression LTD.

Both benzamides facilitated the formation of stable potentiation induced with three-pulse burst stimulation which is normally ineffective. Burst response analysis revealed that CX greatly prolonged the duration of depolarization by slowing the decay of the response which thus presumably leads to a more continuous N-methyl-D-aspartate NMDA receptor activation. Cyclothiazide was ineffective in increasing maximal potentiation in either field or whole-cell recordings.

These results suggest that 1 modulation of AMPA receptors which increases either response amplitude or duration can facilitate LTP formation, 2 modulators that effectively slow response deactivation augment the maximum magnitude of LTP and LTD, and 3 receptor desensitization may have a minor impact on synaptic plasticity in the hippocampus.

Taken together, our data indicate that AMPA receptor modulators differ substantially in their ability to enhance synaptic potentiation or depression, depending on their particular influence on receptor kinetics, and hence that they may also be differentially effective in influencing higher-order processes such as memory encoding. Arai, Amy C.

The present study analyzed the effects of an ampakine CX; 2H,3H, 6aH-pyrrolidino[2",1"-3',2']1,3-oxazino[6',5'-5,4]benz o[e]1, 4-dioxanone that belongs to a benzoxazine subgroup characterized by greater structural rigidity and higher potency. CX enhanced the size amplitude and duration of field excitatory postsynaptic potentials in hippocampal slices and autaptically evoked excitatory postsynaptic currents in neuronal cultures with EC 50 values of 20 to 40 microM.

Currents through homomeric, recombinant AMPA receptors were enhanced with EC 50 values that did not differ greatly across GluR flop subunits microM but revealed slightly lower potency at corresponding flip variants. Competition experiments using modulation of [ 3 H]fluorowillardiine binding suggested that CX and cyclothiazide share a common binding site but cyclothiazide seems to bind to an additional site not recognized by the ampakine.

CX did not reverse the effect of GYKI on responses to brief glutamate pulses, which indicates that they act through separate sites, a conclusion that was confirmed in binding experiments.

In sum, these results extend prior evidence that ampakines are effective in enhancing synaptic responses, most likely by slowing deactivation, and that their effects are exerted through sites that are only in part shared with other modulators. J Pharmacol Exp Ther. Epub Jul The present study examined this apparent refractory period and the possibility that spaced ampakine treatments could sustain elevated BDNF protein levels. Western blots confirmed that after an extended period of ampakine treatment, AMPA receptor protein levels are indeed reduced, suggesting that with longer treatments receptor down-regulation mediates ampakine insensitivity.

These results suggest that spaced ampakine treatments can be used to sustain elevated neurotrophin levels and to test the utility of this manipulation for neuroprotection by endogenous neurotrophins. Acute effects of CX were dose dependent over the range in which the drug increased synchronous neuronal discharges; threshold concentrations for acute responses had large effects on mRNA content when applied for 3 d. Comparable results were obtained with a second, structurally distinct ampakine CX Antagonism of L-type voltage-sensitive calcium channels blocked induction in entorhinal cortex but not hippocampus.

Prolonged infusions of suprathreshold ampakine concentrations produced peak BDNF mRNA levels at 12 hr and a return to baseline levels by 48 hr. In contrast, BDNF protein remained elevated throughout a 48 hr incubation with the drug. Nerve growth factor mRNA levels also were increased by ampakines but with a much more rapid return to control levels during chronic administration. The present results provide evidence of regional differences in mechanisms via which activity regulates neurotrophin expression.

Moreover, these data establish that changes in synaptic potency produce sufficient network level physiological effects for inducing neurotrophin genes, indicate that the response becomes refractory during prolonged ampakine exposure, and raise the possibility of using positive AMPA modulators to regulate neurotrophin levels in aged brain.

Effect of AMPA receptor modulators on hippocampal and cortical function. Eur J Pharmacol Apr 7; 1 "Attention has focused on drugs that modulate AMPA alpha-aminohydroxymethylisoxazole proprionic acid receptors because of their potential for enhancing memory and treating certain pathologies that involve glutamatergic neurotransmission.

The aim of this study was to compare and contrast the functionality of positive allosteric modulators of AMPA receptors in the hippocampus and medial prefrontal cortex. Electrically stimulated EPSPs excitatory postsynaptic potential in the hippocampus were augmented by CX [ 1-quinoxalineylcarbonyl piperidine], aniracetam and 1-BCP [ 1- 1,3-benzodioxolylcarbonyl piperidine] and not by cyclothiazide.

Using grease gap electrophysiology, it was found that the mode of application dramatically altered the effect of the modulators of AMPA-induced depolarization.

However, in the hippocampus, only aniracetam and cyclothiazide augmented the response when simultaneously added to AMPA. Therefore, in addition to regional variations, there appears to be differences in modulator response dependent upon whether a response is generated endogenously or exogenously by AMPA. The waveform of synaptic transmission at hippocampal synapses is not determined by AMPA receptor desensitization. Brain Res Jul 20; 2 "Relationships between the kinetic properties of AMPA receptors and the decay phase of fast excitatory transmission were investigated using modulatory drugs.

The benzothiadiazide compound cyclothiazide blocked receptor desensitization in patches excised from hippocampus but had only a weak influence on receptor deactivation, i. The ampakine drug CX BDP produced an opposite pattern of effects: a fourfold slowing of deactivation with little change in desensitization.

A structurally related drug CX or BDP had prominent effects on both desensitization and deactivation. These results indicate that receptor deactivation plays a substantially greater role than receptor desensitization in determining the duration of synaptic responses. Brent D. Holst, Peter W.

Vanderklish, Leslie A. Krushel, Wei Zhou, Ronald B. Langdon, John R. McWhirter, Gerald M. Edelman, and Kathryn L. Ampakines are a class of drugs that modulate neurotransmitters in the brain. The name is partially derived from AMPA, a-aminohydroxymethylisoxazolepropionic acid receptor structure in brain neurons. The drugs influence how those receptors get signals. They "attenuate desensitization of AMPA receptor currents". Neurotransmitters bind to proteins, called receptors, located on the surface of the receiving neurons.

This binding then triggers subsequent cellular events in the receiving neurons. Ampakines influence the receptors. Ampakines enhance the functioning of a receptor, called the AMPA receptor , which plays a key role in memory formation and communication within and between different regions of the brain.

One article put it this way : " Brain imaging in primates has shown that ampakines expand cortical networks engaged by a complex task; coupled with behavioral data, these findings provide evidence for the possibility of generating new cognitive capabilities.

The hope and promise of ampakines is that they will produce cognitive benefits when used as drugs. There is research interest in memory enhancement, stroke therapy, Alzheimers treatment, sleep deprivation aid, and other therapeutic uses of ampakines. It is known that racetams act as ampakines by stimulating the Glutmatic systems. Some racetams seem to have a higher affinity to activation of the AMPA and NDMA receptors however it is not sure how effective each racetam is as they also act of the Acetycholine system.

This makes it hard to determine which nootropic method of action is more prevalent as Acetylcholine receptor stimulation also contributes to improved cognition. The CX class share the benzoylpiperidine and benzoylpyrrolidine structure. Animal and human trials have been conducted on several of the CX drugs. Animal trials showed great promise however human trials showed poor results due to low potency and short half-life. CX is much stronger than the previous CX compounds.

According to their studies, CX has great benefits in treating both however the FDA has put their application on hold due to tissue toxicology in animal models. Cortex has stated CX as safe and well tolerated in humans however more evidence needs to be submitted to the FDA before it is brought to market as an ampakine or nootropic drug. Very little information has been released about CX by Cortex Pharmaceutical, however it has been proposed to be 5x more potent than CX We are likely to see more of the CX ampakine nootropic in the future.

Eli Lilly Pharmaceuticals was the first company to bring Penicillin and human insulin to market and they have been focusing specifically on the LY Class of ampakine drugs.