What Are Ampakines, and What Types of Ampakines Are There?

Ampakines belong to the category of nootropic compounds that enhance learning and memory. They are molecules that stimulate α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type ionotropic glutamate receptors. The AMPA receptor subunits are distributed differentially in the brain and therefore different Ampakines can act on different regions of the brain as they exhibit subunit preference.

Stimulation of AMPA receptors by Ampakines results in enhancement of fast, excitatory transmission. Ampakines have been shown to slow deactivation and attenuate desensitization of AMPA receptor currents, and facilitate long-term potentiation (LTP). Ampakines also enhance production of neurotrophic factors such as Brain-derived neurotrophic factor (BDNF).

These properties make Ampakines suitable for enhancing memory. Those with cognitive disorders typically have impaired Glutamatergic transmission. Therefore, improvement of glutamatergic transmission by Ampakines can potentially correct these cognitive defects. Preclinical studies show that Ampakines have positive effects on various tests for memory and cognition. These early findings suggest that Ampakines can help overcome cognitive impairment. The potential benefits to neurological conditions including Parkinson’s disease, attention-deficit hyperactivity disorder, and schizophrenia are what fuels research and development for Ampakines.

Side Effects of Ampakines

CNS hyperexcitability due to increased AMPA receptor activities is a potential side effect of Ampakines. Low-impact and high-impact are the two main classifications for Ampakines. Low-impact Ampakines may cause lower hyper-excitability compared to high-impact Ampakines. High-impact Ampakines are more potent, but low-impact offer a broader therapeutic window(1). Overall, few side effects have been determined. Reports vary based on the Ampakine consumed and the individual. However, headaches, impaired episodic memory, and nausea are on the list of potential side effects of Ampakines.

Several types of Ampakines exist. This post covers research on many of the Ampakines investigated in various models of cognitive impairment. We will discuss the underlying mechanisms of function of some of these Ampakines.


Also known as DM235, Sunifiram is a nootropic drug, similar in structure to, and four times more potent than Piracetam. Sunifiram has been shown to enhance cognition in rodents partaking in the Morris water maze (MWM) or Morris water navigation task(2). Sunifiram at a concentration of 10 to 100 nM dramatically enhanced LTP via stimulation of the glycine-binding site of NMDAR(3) in mouse hippocampal slices. In another study, it was found that Sunifiram improved cognitive deficits in olfactory bulbectomized (OBX) mice, an animal model of depression. It also enhanced LTP induction, and this effect was mediated by a glycine-binding site of N-methyl-d-aspartate receptor (NMDAR) activity(4). Sunifiram also prevented amnesia induced by scopolamine using a passive avoidance test in mice(2). More information about this Ampakine is available in our Sunifiram review.


Unifiram or DM232 was found to produce results comparable to Sunifiram in animal studies. Like Sunifiram, Unifiram overcame memory disruption by scopolamine in the passive avoidance test(5). Unifiram also significantly reduced the total sleeping time induced by pentobarbital in mice in the same study.

CX-516 (Ampalex)

CX516 (Ampalex) is one of the AMPA modulators currently being developed by Cortex, collaborating with Shire and Servier. It could potentially treat schizophrenia, mild cognitive impairment, and Alzheimer’s disease. CX516 caused enhancement of performance in a spatial short-term memory task using delayed-nonmatch-to-sample (DNMS) task in rats, a task for measuring short-term memory(6). Another study demonstrated that CX516 ameliorates glutamatergic synaptic dysfunction caused by chloroquine-induced lysosomal disruption, which causes protein accumulation(7).


CX546-treated organotypic hippocampal slices showed prolonged and enhanced potentiation upon LTP induction. CX546 improved the disrupted latent inhibition in mGluR5 knockout mice (a mouse model of schizophrenia) and facilitated latent inhibition in control(8). CX546 has also shown efficacy in other applications such as reversing the respiratory depression produced by sedative drugs such as opioids(9).


In a study that examined the effect of CX614 on excitatory synaptic transmission, CX614 increased the field excitatory postsynaptic potentials, at very low concentration, in hippocampal slices. CX614 also increased the affinity of AMPA receptors for agonists such as [3H] Fluorowillardiine(10). It was also found to increase mRNA expression of BDNF in cultured hippocampal slices.

CX-691 (Farampator)

Farampator is more potent than CX516 in increasing the slope of field excitatory postsynaptic potentials (fEPSPs) in rat hippocampal slices. Farampator potentiates AMPA receptor-mediated responses in vitro systems and enhances hippocampal long-term potentiation. In a double-blind, placebo-controlled, randomized study using healthy elderly volunteers, 500 mg Farampator caused a significant improvement in short-term memory but appeared to impair episodic memory(11). In a rodent model, CX691 administered either in an acute manner or at sub-chronic level was found to attenuate impairment of cued fear conditioning caused by scopolamine. While acute CX691 increased dopamine in the medial prefrontal cortex, and extracellular levels of acetylcholine in the dorsal hippocampus and medial prefrontal cortex, sub-chronic administration of CX691 elevated BDNF mRNA expression in the hippocampus(12).


CX717 was found to cause marked improvements in the performance of monkeys on a task where monkeys visualize a ‘clip art’ image on a computer and after a lag, are required to select it from a set of similar figures(13). CX717 was unable to enhance the cognitive abilities of humans presented with night shift work simulation(14) even though CX717 reversed impaired performance in sleep-deprived rhesus monkeys(15). In a study involving the performance of control vs. cognitively deficient rats (using bilateral vestibular deafferentation), in an object recognition memory task and five-choice serial reaction time task (5CSRTT), CX717 reduced the number of incorrect responses in 5CSRTT in both sham and BVD rats. However, CX717 produced an unfavorable effect in the object recognition memory task(16).


A member of biaryl propyl sulfonamides, LY392098 is a highly potent, selective and centrally active, positive modulator of native AMPA receptors. In one of the studies, LY392098 enhanced the AMPA-evoked responses in prefrontal cortex neurons. Also, it also enhanced the affinity of the agonist for the receptors(17). LY392098 also caused a concentration-dependent increase in mRNA encoding BDNF(18).


Both in-vitro and in vivo, LY404187 has been proven to enhance glutamatergic synaptic transmission. Examination of the different recombinant human homomeric AMPA receptors revealed that the activity of all subtypes of receptors was potentiated by LY404187 in a concentration-dependent manner. At the molecular level, LY404187 increases cerebral glucose utilization and c-fos expression in the rat, providing the mechanistic basis for the cognitive enhancing effects of this Ampakine(19). LY404187 was also tested in rodent models of Parkinson’s disease(PD) and was found to provide protection (neurochemical and histological) against the unilateral infusion of 6-hydroxydopamine into the substantia nigra or striatum of rats, a compound widely used to lesion the nigrostriatal dopaminergic system as a model of PD.


LY451646 was found to have antidepressant-like effect in mice in a forced swim test, a widely used animal model of antidepressant action(20). Another study showed that LY451646 treatment increased progenitor cell proliferation in the dentate gyrus of the hippocampus, a region involved in learning and memory. This study shed some light on the underlying mechanism for the antidepressant-like activity of LY451646(21).


Similar to LY404187, LY503430 has also been found to provide dose-dependent functional and histological protection in animal models of Parkinson’s disease. The same study showed that LY503430 produced an increase in brain-derived neurotrophic factor (BDNF) in the substantia nigra and growth associated protein-43 (GAP-43) in the striatum.


IDRA-21 enhances learning and memory in normal animals, both in rodent and primate studies. Oral administration of IDRA-21 improved performance in visual recognition memory in macaques(22). In another study, oral administration of IDRA-21 produced a highly significant improvement in the performance of a delayed matching-to-sample (DMST) task by young adult rhesus monkeys. IDRA-21 also improved task accuracy in aged rhesus monkeys(23).


S18986 was found to reverse the memory deficit in aged mice but did not modify performance in young adult mice as measured by sequential alternation task, a useful tool to reveal age-induced time-dependent working memory impairments(24). S18986 also stimulated BDNF production in the neonatal brain(25). S18986 improved aged mouse performance in the test of long-term/declarative memory flexibility and exerted a beneficial effect on the short-term/working memory test(26). A separate study showed that chronic, oral administration of S18986 increased locomotor activity and performance in a spatial memory task (Y-maze) in aged rodents. Also, chronic S18986 treatment retarded the decline in forebrain cholinergic neurons during aging, which is one of the pathological symptoms of Alzheimer’s disease(27). S18986-1 was also evaluated on cognitive functions by using a one-trial object recognition test in rats. Oral administrations with S18986-1 before each session of the test had improved object recognition at dosages of 0.3 mg/kg or lower, which was ~30 times lower than the active dose of Aniracetam (10 mg/kg administered i.p) under the same conditions(28).

Org 26576

In a translational study(29), Org 26576 was found to produce inhibition of locomotor hyperactivity in 6-hydroxydopamine-lesioned rats. In treating ADHD symptoms of adult subjects, Org 26576 outperformed the placebo. Most frequently reported adverse effects of Org 26576 were nausea, dizziness, and headache. In a phase 1b trial, Org 26576 demonstrated good tolerability and pharmacokinetic properties in depressed patients(30). Org 26576 was also found to induce expression of BDNF in the hippocampus in the presence of stress during swim stress session(31). A study evaluated the actions of subchronic Org 26576 administration on spatial reference memory performance in the 5-day Morris water maze task in rats. Org 26576 significantly improved spatial memory storage and retrieval and in particular enhanced search accuracy during reference memory retrieval(32). Furthermore, chronic administration of Org 26576 was found to increase progenitor cell proliferation in the dentate gyrus in the hypothalamus and prelimbic cortex(33).

Are Ampakines the future of cognitive enhancement?

Ampakines have delivered promising results in enhancing cognitive functions in preclinical studies in rodent and primate models, and in some cases, in human subjects. Thus, Ampakines are good candidates for the treatment of cognitive impairment related disorders, especially those with reduced level of glutamate-mediated excitatory stimulation including Alzheimer’s disease and schizophrenia. Further studies are needed to understand how Ampakines affect brain functions and to determine the safety and efficacy of these drugs for long-term use.

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~ Arthur Schopenhauer

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