The molecular targets of Pramiracetam are not fully elucidated but are believed to involve multiple neurotransmitter systems and receptors. As a racetam-class nootropic, Pramiracetam is thought to modulate glutamatergic signaling, particularly through AMPA receptors and metabotropic glutamate receptors. It may also enhance cholinergic neurotransmission, as racetams have been shown to increase acetylcholine release and improve cholinergic function. Pramiracetam has been reported to inhibit prolyl endopeptidase (PREP), an enzyme involved in the metabolism of neuropeptides, which could contribute to its cognitive-enhancing effects. The compound may also interact with various neurotransmitter receptors including nicotinic acetylcholine receptors, dopamine receptors, and serotonin receptors. Additionally, Pramiracetam may improve cerebral blood flow and oxygen utilization, indirectly supporting cognitive function through enhanced brain metabolism. The diisopropylaminoethyl moiety may confer enhanced binding affinity or selectivity for specific targets compared to piracetam, contributing to its higher potency.

In vitro activity of Pramiracetam is characterized by its effects on neurotransmitter release and receptor modulation. In brain slice preparations and synaptosomal preparations, Pramiracetam has been shown to enhance the release of acetylcholine and glutamate in various brain regions including the hippocampus and cerebral cortex. The compound increases [³H]acetylcholine release from hippocampal slices in a concentration-dependent manner, with EC50 values in the low micromolar range. In receptor binding assays, Pramiracetam shows low affinity for most classical neurotransmitter receptors, suggesting that its mechanism of action may involve indirect modulation of receptor function rather than direct receptor binding. The compound has been shown to enhance AMPA receptor-mediated synaptic transmission in hippocampal neurons, which may underlie its cognitive-enhancing effects. In cell culture models of neuronal injury, Pramiracetam has shown neuroprotective effects against excitotoxicity and oxidative stress. Specific IC50 and EC50 values for Pramiracetam's in vitro activities vary depending on the assay system and the parameter measured.

The effect of systemic administration of pramiracetam on neuronal type nitric oxide synthase (NOS) activity and NOS mRNA expression were studied in the hippocampus and cerebral cortex in rats. A dose of 300 mg/kg (i.p.) of this nootropic produced an approximately 20% increase in NOS activity in rat brain cortical homogenates but not in hippocampal homogenates; no significant changes were observed in NOS mRNA expression in the cortex and hippocampus. A lower dose of pramiracetam (100 mg/kg i.p.) was ineffective on NOS mRNA expression and enzyme activity. Interestingly, administration of pramiracetam (300 mg/kg i.p.) in rats pretreated (24 h before) with lithium chloride (LiCl) (3 mEq/kg i.p.) yielded a 40% increase in cortical NOS activity. However, in LiCl-pretreated rats this nootropic failed to affect cortical NOS mRNA expression; LiCl (3 mEq/kg i.p.) given alone produced no effect. In conclusion, the present data demonstrate that pramiracetam given alone or in combination with LiCl increases NOS activity in brain cortical homogenates of rats and this may contribute to the mechanisms underlying learning and memory improvement produced by this nootropic.
In vivo activity of Pramiracetam has been demonstrated in various animal models of cognitive impairment. In rodent models of Alzheimer's disease (e.g., scopolamine-induced amnesia, Aβ-induced cognitive deficits), Pramiracetam administered orally or intraperitoneally at doses of 10-100 mg/kg significantly improves performance in memory tasks including the Morris water maze, passive avoidance, and novel object recognition tests. The compound has also shown efficacy in models of traumatic brain injury, improving cognitive recovery and reducing neurological deficits. In models of aging-related cognitive decline, Pramiracetam has been shown to reverse age-associated memory impairments. The compound's amnesia-reversal activity has been demonstrated in various pharmacological models of memory impairment. Pramiracetam is more potent than piracetam, with effective doses typically 5-10 times lower than those of piracetam. In clinical studies, Pramiracetam has shown efficacy in improving cognitive function in patients with dementia, age-related cognitive decline, and post-electroconvulsive therapy cognitive deficits.

For in vitro neurotransmitter release assays with Pramiracetam, the following protocol is used: hippocampal slices (400 μm thick) are prepared from adult rats and pre-loaded with [³H]choline to label the acetylcholine pool. Slices are superfused with Krebs-Ringer buffer at 37°C, and the efflux of radioactivity is measured using a fraction collector. Pramiracetam is added to the superfusion buffer at concentrations of 0.1-100 μM, and the release of radioactivity is stimulated by increasing the potassium concentration (20-50 mM) or by electrical stimulation. The amount of evoked [³H]acetylcholine release is calculated as a percentage of the total tissue radioactivity. For glutamate release assays, synaptosomal preparations are used, and glutamate release is measured by HPLC-ECD. For receptor binding assays, membrane preparations from rat brain are incubated with various radioligands (for AMPA receptors, NMDA receptors, nicotinic receptors, etc.) and varying concentrations of Pramiracetam (0.01-1000 μM). Bound radioactivity is measured by scintillation counting after filtration, and Ki values are calculated from competition binding curves.

For in vitro cell-based assays with Pramiracetam, the following typical protocol is used: primary hippocampal neurons from embryonic rats are cultured in Neurobasal medium with B27 supplement at 37°C in 5% CO₂ for 7-14 days. Cells are treated with Pramiracetam at concentrations of 0.1-100 μM for 24-48 hours. For neuroprotection studies, cells are exposed to excitotoxic insults (e.g., glutamate 10-100 μM or Aβ 1-42 10 μM) in the presence or absence of Pramiracetam, and cell viability is assessed by LDH release assay or MTT assay. For studies on synaptic plasticity, neurons are treated with Pramiracetam and the expression of synaptic proteins (e.g., PSD-95, synaptophysin, GluA1) is measured by Western blotting. For studies on neurite outgrowth, neurons are treated with the compound and neurite length is measured using ImageJ after immunostaining with anti-MAP2 antibody. For studies on calcium signaling, neurons are loaded with Fura-2 or Fluo-4, and intracellular calcium levels are measured by ratiometric imaging or flow cytometry in response to various stimuli.

For in vivo animal studies with Pramiracetam, the following general protocol is used: male Wistar rats (8-12 weeks old, 200-250 g) or male C57BL/6 mice (8-12 weeks old, 20-25 g) are used. For the Morris water maze test, rats are trained to find a hidden platform in a pool of water over 4-5 days (4 trials per day). On the probe trial (day 6), the platform is removed and the time spent in the target quadrant is recorded. Pramiracetam is administered orally at doses of 10, 30, and 100 mg/kg 30-60 minutes before each training session. For the passive avoidance test, rats are trained in a two-compartment apparatus: the animal is placed in the light compartment and receives a foot shock (0.5 mA, 1-2 seconds) upon entering the dark compartment. Retention is tested 24 hours later, and the latency to enter the dark compartment is recorded. For scopolamine-induced amnesia models, scopolamine (1-2 mg/kg, i.p.) is administered 30 minutes before training. For traumatic brain injury models, rats are subjected to controlled cortical impact or fluid percussion injury, and Pramiracetam is administered daily for 2-4 weeks post-injury. Cognitive function is assessed using various behavioral tests.

The pharmacokinetic properties of Pramiracetam have been characterized in humans and animals. After oral administration, Pramiracetam is absorbed with a bioavailability of approximately 80-90% in humans. Peak plasma concentrations are reached within 1-2 hours (Tmax). The compound has a volume of distribution of approximately 1-2 L/kg, indicating distribution into total body water. Plasma protein binding is low (approximately 20-30%). The elimination half-life is approximately 4-6 hours in humans. Pramiracetam is metabolized primarily in the liver by cytochrome P450 enzymes, though the specific isoforms involved have not been fully characterized. The compound and its metabolites are excreted primarily in the urine. Pramiracetam's pharmacokinetics are linear over the therapeutic dose range, and no significant accumulation occurs with repeated dosing. The compound is not significantly affected by food intake. In animal studies, Pramiracetam shows good brain penetration, consistent with its cognitive-enhancing effects.

The toxicity profile of Pramiracetam is favorable based on clinical use and preclinical studies. The compound has a wide therapeutic index with low acute toxicity: the oral LD50 in rodents is greater than 2000 mg/kg. In sub-chronic and chronic toxicity studies, Pramiracetam has not shown significant organ toxicity at clinically relevant doses. Common side effects in humans are mild and include headache, nausea, dizziness, and irritability. Serious adverse effects are rare. Pramiracetam is not mutagenic in standard genotoxicity tests (Ames test, micronucleus test) and is not carcinogenic in long-term studies. The compound has a low potential for drug-drug interactions due to its limited effects on cytochrome P450 enzymes. Pramiracetam is not recommended during pregnancy and lactation unless the potential benefit justifies the potential risk to the fetus or infant. The compound's safety profile makes it suitable for use in elderly patients and those with cognitive impairments.

Neurology.1991Apr;41(4):570-4;Funct Neurol.1995 May-Jun;10(3):151-5.

Pramiracetam is an organonitrogen and organoxazone compound whose function is related to α-amino acids. Pracilstein has previously been approved for marketing in some Eastern European countries under brand names such as Pramistar, Neupramir, and Remen. It has also received orphan drug designation in the United States. Pracilstein has been investigated for the treatment of Alzheimer's disease and as an adjunct therapy for the recovery of cognitive function in patients with major depressive disorder after electroconvulsive therapy (ECT).
Pramiracetam (CAS# 68497-62-1) is a high-potency racetam-class nootropic derived from piracetam with a molecular formula of C14H27N3O2 and a molecular weight of 269.38 g/mol. It is a CNS drug that improves memory and has amnesia-reversal activity. It has been studied for Alzheimer's disease and post-ECT cognitive restoration and can improve cognitive deficits associated with traumatic brain injuries. It is also known as Amacetam, Ectapram, Neupramir, and Remen. Future research could explore its mechanisms of action, particularly its effects on synaptic plasticity and neuroprotection, investigate its potential in other neurological disorders such as stroke and Parkinson's disease, and develop novel racetam derivatives with improved potency and selectivity.

C14H27N3O2

269.38

269.21

68497-62-1

51712

White to off-white solid powder

1.0±0.1 g/cm3

461.0±30.0 °C at 760 mmHg

47 °C

232.6±24.6 °C

0.0±1.1 mmHg at 25°C

1.495

0.39

1

3

7

19

308

0

ZULJGOSFKWFVRX-UHFFFAOYSA-N

InChI=1S/C14H27N3O2/c1-11(2)17(12(3)4)9-7-15-13(18)10-16-8-5-6-14(16)19/h11-12H,5-10H2,1-4H3,(H,15,18)

N-(2-(diisopropylamino)ethyl)-2-(2-oxopyrrolidin-1-yl)acetamide

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.28 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.28 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly.
Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.

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Solubility in Formulation 3: ≥ 2.5 mg/mL (9.28 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 4: 12.5 mg/mL (46.40 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)