7491-74-9 Usage
Uses
Used in Pharmaceutical Industry:
Piracetam is used as a nootropic agent for improving cognitive function and as an adjunctive treatment for myoclonus of cortical origin and tardive dyskinesia.
Used in Research:
Piracetam is used as a subject for studying crystal structure and physicochemical properties of six co-crystals, as well as for investigating its in vitro antioxidant properties.
Used in Antinauseant Applications:
Piracetam is used as an antinauseant to help alleviate nausea and vomiting in patients.
Indication
It is indicated in the case of adult patients suffering from myoclonus of cortical origin, irrespective of aetiology, and should be used in combination with other anti-myoclonic therapies.
Pharmacological effects
Neuronal effects
Piracetam has important effects on neurotransmission that are not limited to any one type of neurotransmitter. It has been shown to influence cholinergic[3,4], serotoninergic[5], noradrenergic[6], and glutamatergic[7] systems. The modulation of these systems by piracetam does not result from direct receptor agonism or antagonism(piracetam has no affinity for these receptors; Ki > 10 μM)[8]. Instead, piracetam appears to increase the number of postsynaptic receptors and or restore the function of these receptors. The effect of piracetam on cholinergic and glutamatergic systems is likely to be particularly relevant to its clinical benefit in cognitive disorders, given the increasing evidence that dysfunction in these systems may be related to cognitive decline[9,10]. Preclinical studies have shown that piracetam appears to offer neuroprotective benefits. This is consistent with the suggestion that interactions between piracetam and membrane lipids may decrease the risk of membrane fusion[11]. Piracetam has been shown to reduce the incidence of animal death following barbiturate overdose, and to protect against morphological changes related to long-term alcohol use[12]. The anticonvulsant action of piracetam has also been documented in animal studies. Administration of piracetam prior to a convulsant stimulus reduces seizure severity in rats prone to audiogenic attacks[13].
Vascular effects
Studies suggest that piracetam exerts a number of effects on erythrocytes, such as decreased adhesion to endothelium[14]. These effects are likely to facilitate movement of erythrocytes through the circulation. Studies have also indicated that piracetam exerts an effect on blood vessels. For example, in vitro, 2 mg/kg piracetam decreased the time taken for rabbit pial vessels to return to normal diameter following a period of induced arteriolar spasm(10.4 vs. 5.1 min for 0.02 and 2 mg/kg of piracetam, respectively)[15]. Piracetam may also influence blood coagulation. In healthy humans, a single dose of piracetam(3.2 to 9.6 g)?reduced plasma levels of fibrinogen and von Willebrand factor in a dose-dependent manner by up to 40%[16]. Enhanced cerebral blood flow has been reported following piracetam treatment in hypotensive cats and in humans with acute cerebral ischemia[17,18]. Additionally, piracetam appears to influence microcirculation at the peripheral level. Following treatment with piracetam, renal blood flow was significantly greater in ischemically damaged rat kidneys relative to controls[19], and, in a separate experiment, blood flow significantly increased in the cochlea of guinea pigs without any marked change in blood pressure[20].
Pharmacokinetics
Piracetam is rapidly absorbed. Following oral administration, peak plasma concentrations in fasting subjects are achieved in approximately 30 min[22]. Following a single oral dose of 3.2 g, peak concentration is typically 84 ug/mL. Oral formulations of piracetam are extensively absorbed with a bioavailability close to 100%[22]. No metabolites of piracetam have yet been discovered and the drug is excreted unchanged in the urine by glomerular filtration[21]. While food does not affect the extent of absorption of piracetam, it does decrease the maximal plasma concentration of the drug by 17% and prolong Tmax to 1.5 h. Piracetam crosses blood–brain and placental barriers and is found in all tissues, except adipose tissue. The uptake into the brain is less rapid than into the circulation, and, at nearly 8 h, half-life in cerebrospinal fluid is longer than in plasma(about 5 h)[21].
Mode of action
Although piracetam is a derivative of GABA, its mechanism of action appears to be unrelated to the properties of this neurotransmitter. While the exact mode of action of piracetam is a matter of debate, there is increasing evidence that its underlying effect is to restore cell membrane fluidity. Cell membranes comprise a bilayer of lipid molecules interspersed with protein molecules. These membranes are fluid structures in which the molecules comprising the membrane can diffuse while maintaining this overall arrangement. Membrane fluidity is believed to be important for a number of activities including membrane transport, enzyme activity, chemical secretion, and receptor binding and stimulation[23,24]. Piracetam can have direct interaction with the membrane. The resultant mobile drug–lipid complexes are thought to induce the reorganization of lipids, which may influence membrane function and fluidity[25]. Studies have also demonstrated that piracetam influences membrane fluidity, particularly when normal fluidity is compromised, as is often seen during aging[26]. Several in vitro studies have assessed fluidity during piracetam treatment using anisotropy of membrane-bound DPH[1,6-diphenyl-1,3,5-hexatriene]. Incubation with piracetam restored fluidity in brain membranes of elderly mice with diminished fluidity but had no effect on brain membranes of younger mice with normal fluidity[27]. Similarly, in other studies using in vitro anisotropy techniques, fluidity was restored in the membranes of aged rat and aged human brains following incubation with piracetam[27]. Similar effects were observed in hippocampal membranes from patients with Alzheimer’s disease[28]. This improvement of fluidity coincided with significantly improved avoidance learning[27]. No effect of piracetam on learning or membrane fluidity was found in young rats receiving piracetam. Through restored membrane fluidity, piracetam can promote restored neurotransmission such as glutamatergic and cholinergic systems, enhances neuroplasticity and mediates neuroprotective and anticonvulsant effects at the neuronal level. It has also been found that piracetam can also improves the fluidity of platelet membranes and decreases adhesion of erythrocytes to cell wall as well as reduces vasospasm which in turn improves microcirculation including cerebral and renal blood flow[23,24].
Toxicity
Piracetam is remarkably well tolerated. In preclinical trials, no irreversible toxicity was reported in mice, rats or dogs receiving single oral doses of up to 10 g/kg. In a pooled analysis of 91 double-blind, placebo-controlled studies, hyperkinesia, weight gain, nervousness, somnolence, depression and asthenia were slightly increased with piracetam, although the incidence of each of these events was less than 2%.
Contradictions and drug interactions
Due to its renal clearance, piracetam dose should be adjusted in patients with renal insufficiency and the drug is contraindicated in patients with end-stage renal disease. Piracetam should not be prescribed to patients with cerebral hemorrhage. While reproductive studies in animals have not identified any risk to the fetus, studies in humans have not been conducted and so the use of piracetam in pregnant or lactating women should be avoided. Piracetam is neither metabolized by the liver nor bound to plasma albumin. The potential for drug–drug interactions is, therefore, low. Although piracetam enhances the anticonvulsant effects of carbamazepine, no interactions with sodium valproate have been reported[29]. There are no known interactions of piracetam with any other drugs.
Side effects
Despite that piracetam is regarded as a relatively safe nootropic, some users may still experience side effects and adverse reactions[30]. The severity and number of side effects experienced from piracetam is subject to significant individual variation. One user may not perceive any side effects, while another may notice severe adverse reactions. Of all those reported piracetam side effects, the most common include: nervousness, increased body movements(hyperkinesia), and weight gain. Some rare cases may also include agitation, anxiety, brain fog, cognitive impairment, depression, fatigue, hemocrit/hemoglobin levels change, headaches, hyperkinesia, insomnia, irritability, libido increase, lightheadedness, muscle spasms, nausea, restlessness, shakiness, sleep disturbances, speech impairment, somnolence, sweating, visual change and weakness.
References
Giurgea C. Vers une pharmacologie de l’activite? inte?grative du cerveau. Tentative du concept nootrope en psychopharmacologie. [Towards an integrative pharmacology of the activity of the brain. Attempt at the nootropic concept in psychopharmacology]. Actual Pharmacol[Paris] 1972;25:115–176.
Winnicka, K., Tomasiak, M., & Bielawska, A.[2005]. Piracetam--an old drug with novel properties? Acta Poloniae Pharmaceutica, 62(5], 405.
Mu?ller WE. Age related quantitative and qualitative receptor changes and pharmacological reactivity. In: Racagni G, Mendlewicz J, Eds. Treatment of age-related cognitive dysfunction: Pharmacological and clinical evaluation. Int Acad Biomed Drug Res. Basel: Karger 1992;2:35–40.
Pilch H, Mu?ller WE. Piracetam elevates muscarinic cholinergic receptor density in the frontal cortex of aged but not of young mice. Psychopharmacology 1988;94:74–78.
Valzelli L, Bernasconi S, Sala A. Piracetam activity may differ according to the age of the recipient mouse. Int Pharmacopsychiatry 1980;15:150–156.
Olpe H-R, Steinmann MW. The activating action of vincamine, piracetam and hydergine on the activity of the noradrenergic neurons of the locus coeruleus. Behav Neural Biol 1981;33:249–251.
Cohen SA, Mu?ller WE. Effects of piracetam on N-methyl-D-aspartate receptor properties in the aged mouse brain. Pharmacology 1993;47:217–222
Gualtieri F, Manetti D, Romanelli MN, Ghelardini C. Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs. Curr Pharm Des 2002;8:125–138.
Segovia G, Porras A, Del Arco A, Mora F. Glutamatergic neurotransmission in aging: A critical perspective. Mech Ageing Dev 2001;122:1–29.
Terry AV Jr, Buccafusco JJ. The cholinergic hypothesis of age and Alzheimer’s disease-related cognitive deficits: Recent challenges and their implications for novel drug development. J Pharmacol Exp Ther 2003; 306:821–827.
Mingeot-Leclercq M-P, Lins L, Bensliman M, et al. Piracetam inhibits the lipid-destabilising effect of the amyloid peptide Aa? C-terminal fragment. Biochim Biophys Acta 2003;1609:28–38.
Brandao F, Paula-Barbosa MM, Cadete-Leite A. Piracetam impedes hippocampal neuronal loss during withdrawal after chronic alcohol intake. Alcohol 1995;12:279–288.
Benesova O. The effects of nootropic drugs on the susceptibility to audiogenic seizures in rats. Act Nerv Super[Praha] 1980;22:192–193.
Nalbandian RM, Henry RL, Burek CL, et al. Diminished adherence of sickle erythrocytes to cultured vascular endothelium by piracetam. Am J Hematol 1983;15:147–151.
Reuse-Blom S. Microcirculation of the pial vessels in the rabbit. Acta Cardiol 1979;34:35–36.
Moriau M, Crasborn L, Lavenne-Pardonge E, Von Frenckell R, Col-Debeys C. Platelet anti-aggregant and rheological properties of piracetam. Arzneimittelforschung 1993;43:110–118.
Herrschaft H. The effect of piracetam on global and regional cerebral blood flow in acute cerebral ischemia of man. Med Klin 1978;73:195–202.
Sato M, Heiss WD. Effect of piracetam on cerebral blood flow and somatosensory evoked potential during normotension and hypotensive ischemia in cats. Arzneimittelforschung 1985;35:790–792.
Gianello P, Janssen T, Chatzopoulos C, et al. Beneficial effect of piracetam on renal blood flow in ischemically injured kidneys in the rat. Transplant Proc 1988;20:914–916.
Maass B, Soetanto R. Pru?fung der Wirkung von Piracetam auf die Wasserstoff — Clearance am Innenohr [Examination of the effect of piracetam on the hydrogen clearance to the inner ear]. Laryngorhinootologie 1988;67:132–135.
Gobert JG. Gene?se d’un me?dicament: le piracetam. Me?tabolisation et recherche biochimique. [Genesis of the drug piracetam. Metabolism and biochemical research]. J Pharm Belg 1972;27:281–304.
Gobert JG, Baltes EL. Availability and plasma clearance of piracetam in man. Farmaco 1977;3:84–91.
Alberts B, Bray D, Lewis J, et al. Molecular biology of the cell. Chapter 10. 3rd Edition. New York: Garland publishing Inc., 1994.
Crews FT. Effects of membrane fluidity on secretion and receptor stimulation. Psychopharmacol Bull 1982; 18:135–143.
Peuvot J, Schank A, Deleers M, Brasseur R. Piracetam-induced changes to membrane physical properties. A combined approach by 31P nuclear magnetic resonance and conformational analysis. Biochem Pharmacol 1995;50:1129–1134.
Scheuer K, Stoll S, Paschke U, Weigel R, Mu?ller WE. N-methyl-D-aspartate receptor density and membrane fluidity as possible determinants of the decline of passive avoidance performance in aging. Pharmacol Biochem Behav 1995;50:65–70.
Mu?ller WE, Koch S, Scheuer K, Rostock A, Bartsch R. Effects of piracetam on membrane fluidity in the aged mouse, rat and human brain. Biochem Pharmacol 1997;53:135–140.
Eckert GP, Cairns NJ, Mu?ller WE. Piracetam reverses hippocampal membrane alterations in Alzheimer’s disease. J Neural Transm 1999;106:757–761.
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https://mentalhealthdaily.com/2015/12/18/piracetam-side-effects-adverse-reactions-list/
Originator
Nootropyl, UCB ,France,1972
Manufacturing Process
2-Pyrrolidone is first reacted with sodium hydride, then with ethyl chloroacetate to give ethyl 2-oxo-1-pyrrolidine acetate.A solution of 0.3 mol of ethyl 2-oxo-1-pyrrolidine acetate in 300 ml of methanol, saturated with ammonia at 20° to 30°C, is heated at 40° to 50°C for 5 hours, while continuously introducing ammonia. The reaction mixture is evaporated to dryness and the residue recrystallized from isopropanol. 2-Oxo1-pyrrolidineacetamide is obtained in a yield of 86%. MP 151.5° to 152.5°C.
Therapeutic Function
Psychotropic
Biological Activity
Nootropic that displays cognitive enhancing properties. Proposed to enhance neurotransmission via modulation of ion flux; potentiates Na + influx through AMPA receptors. Facilitates efficiency of cholinergic neurotransmission at muscarinic receptors.
Biochem/physiol Actions
Piracetam (2-oxo-1-pyrrolidinyl-acetamide) is a nootropic drug, which enhances memory and facilitates learning. Piracetam also acts as a vasodilator and improves blood flow. It has a potential to treat cognitive impairment in aging, brain injury, memory and balance problems. In addition, piracetam is also used to treat peripheral vascular disease.
Clinical Use
Myoclonus
Safety Profile
Mildly toxic by ingestion. Whenheated to decomposition it emits toxic fumes of NOx.
Metabolism
Potentially hazardous interactions with other drugs
None known
Purification Methods
This typical nootropic (Alzheimer) drug modulates Na flux in AMPA receptors and is purified by recrystallisation from isoPrOH. [Gouilaev & Senning Brain Research Rev 19 180 1994.]
Check Digit Verification of cas no
The CAS Registry Mumber 7491-74-9 includes 7 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 4 digits, 7,4,9 and 1 respectively; the second part has 2 digits, 7 and 4 respectively.
Calculate Digit Verification of CAS Registry Number 7491-74:
(6*7)+(5*4)+(4*9)+(3*1)+(2*7)+(1*4)=119
119 % 10 = 9
So 7491-74-9 is a valid CAS Registry Number.
InChI:InChI=1/C6H10N2O2/c7-5(9)4-8-3-1-2-6(8)10/h1-4H2,(H2,7,9)
7491-74-9Relevant articles and documents
Aerobic oxidation of primary amines to amides catalyzed by an annulated mesoionic carbene (MIC) stabilized Ru complex
Yadav, Suman,Reshi, Noor U Din,Pal, Saikat,Bera, Jitendra K.
, p. 7018 - 7028 (2021/11/17)
Catalytic aerobic oxidation of primary amines to the amides, using the precatalyst [Ru(COD)(L1)Br2] (1) bearing an annulated π-conjugated imidazo[1,2-a][1,8]naphthyridine-based mesoionic carbene ligand L1, is disclosed. This catalytic protocol is distinguished by its high activity and selectivity, wide substrate scope and modest reaction conditions. A variety of primary amines, RCH2NH2 (R = aliphatic, aromatic and heteroaromatic), are converted to the corresponding amides using ambient air as an oxidant in the presence of a sub-stoichiometric amount of KOtBu in tBuOH. A set of control experiments, Hammett relationships, kinetic studies and DFT calculations are undertaken to divulge mechanistic details of the amine oxidation using 1. The catalytic reaction involves abstraction of two amine protons and two benzylic hydrogen atoms of the metal-bound primary amine by the oxo and hydroxo ligands, respectively. A β-hydride transfer step for the benzylic C-H bond cleavage is not supported by Hammett studies. The nitrile generated by the catalytic oxidation undergoes hydration to afford the amide as the final product. This journal is
TYK2 INHIBITORS AND USES THEREOF
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Paragraph 00766-00767, (2020/06/19)
The present invention provides compounds, compositions thereof, and methods of using the same for the inhibition of TYK2, and the treatment of TYK2-mediated disorders.
Process for synthesizing piracetam (by machine translation)
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Paragraph 0051-0065, (2019/07/16)
The invention belongs to the field, and particularly relates to a novel process. The method comprises the specific steps: mixing glycinamide hydrochloride, phase transfer catalyst, alkali, controlling temperature dropwise adding 4 - chlorobutyryl chloride solution reaction, adjusting pH value, filtering, recycling solvent, solvent treatment residue, crystallization, drying and the like to obtain piracetam. The technological one-step reaction synthesis target compound, raw materials are cheap and easily available, the yield is high, the product quality is good, and the method is suitable for industrial production. (by machine translation)
Diversity-Oriented Synthesis of Heterocycles: Al(OTf)3-Promoted Cascade Cyclization and Ionic Hydrogenation
Liu, Tianqi,Jia, Wenqiang,Xi, Qiumu,Chen, Yonghui,Wang, Xiaojian,Yin, Dali
, p. 1387 - 1393 (2018/02/10)
An efficient and facile method has been developed for the diversity-oriented synthesis of heterocycles. Hexahydrophenoxazines, tetrahydroquinolines, indolines, hexahydrocarbazoles, and lactones were conducted via Al(OTf)3-promoted cascade cyclization and ionic hydrogenation. Furthermore, this protocol was utilized to smoothly prepare piracetam and its key intermediate as well.
Bifunctional organometallic catalysts for selective hydration of nitriles to amides
Singh, Kuldeep,Sarbajna, Abir,Bera, Jitendra K.
, p. 853 - 861 (2020/06/26)
In this report, we highlight our recent contributions towards the development of bifunctional catalysts for selective hydration of nitriles to amides.
Ugi Four-Center Three-Component Reaction as a Direct Approach to Racetams
Cioc, R?zvan C.,Schaepkens van Riempst, Lola,Schuckman, Peter,Ruijter, Eelco,Orru, Romano V. A.
, p. 1664 - 1674 (2017/03/21)
We report the synthesis of racetams, a diverse class of small molecule drugs, by means of the Ugi four-center three-component reaction (U4C-3CR). For the first time, γ-aminobutyric acid is employed as bifunctional input in the Ugi reaction. This protocol is simple, general, and allows one-pot access to a range of drugs and bioactive small molecules.
Synthesis of substituted 2-(2-oxopyrrolidin-1-yl)acetamides
Kavina,Sizov,Yakovlev
, p. 873 - 878 (2017/08/02)
The reaction of chloroacetamide with 2 equiv of γ-aminobutyric acid potassium salts provides a convenient method for the synthesis of substituted 4-[(2-amino-2-oxoethyl)amino]butanoic acids. Alkylation products of 2-aminoacetic and 3-aminopropanoic acid with chloroacetamide were isolated. Thermal cyclization of substituted 4-[(2-amino-2-oxoethyl)amino]butanoic acids afforded 2-(2-oxopyrrolidin-1-yl)acetamides.
Hemilability-Driven Water Activation: A NiII Catalyst for Base-Free Hydration of Nitriles to Amides
Singh, Kuldeep,Sarbajna, Abir,Dutta, Indranil,Pandey, Pragati,Bera, Jitendra K.
supporting information, p. 7761 - 7771 (2017/06/06)
The NiII complex 1 containing pyridyl- and hydroxy-functionalized N-heterocyclic carbenes (NHCs) is synthesized and its catalytic utility for the selective nitrile hydration to the corresponding amide under base-free conditions is evaluated. The title compound exploits a hemilabile pyridyl unit to interact with a catalytically relevant water molecule through hydrogen-bonding and promotes a nucleophilic water attack to the nitrile. A wide variety of nitriles is hydrated to the corresponding amides including the pharmaceutical drugs rufinamide, Rifater, and piracetam. Synthetically challenging α-hydroxyamides are accessed from cyanohydrins under neutral conditions. Related catalysts that lack the pyridyl unit (i.e., compounds 2 and 4) are not active whereas those containing both the pyridyl and the hydroxy or only the pyridyl pendant (i.e., compounds 1 and 3) show substantial activity. The linkage isomer 1′ where the hydroxy group is bound to the metal instead of the pyridyl group was isolated under different crystallization conditions insinuating a ligand hemilabile behavior. Additional pKa measurements reveal an accessible pyridyl unit under the catalytic conditions. Kinetic studies support a ligand-promoted nucleophilic water addition to a metal-bound nitrile group. This work reports a Ni-based catalyst that exhibits functional hemilability for hydration chemistry.
Mild and selective heterogeneous catalytic hydration of nitriles to amides by flowing through manganese dioxide
Battilocchio, Claudio,Hawkins, Joel M.,Ley, Steven V.
supporting information, p. 1060 - 1063 (2016/10/17)
A sustainable flow chemistry process for the hydration of nitriles, whereby an aqueous solution of the nitrile is passed through a column containing commercially available amorphous manganese dioxide, has been developed. The product is obtained simply by concentration of the output stream without any other workup steps. The protocol described is rapid, robust, reliable, and scalable, and it has been applied to a broad range of substrates, showing a high level of chemical tolerance.
A general and practical oxidation of alcohols to primary amides under metal-free conditions
Wu, Xiao-Feng,Sharif, Muhammad,Feng, Jian-Bo,Neumann, Helfried,Pews-Davtyan, Anahit,Langer, Peter,Beller, Matthias
, p. 1956 - 1961 (2013/09/24)
A general procedure for oxidation of both benzyl alcohols and alkyl alcohols to primary amides under catalyst free conditions has been developed. 34 examples of primary amides were produced from their corresponding alcohols in moderate to excellent yields. This is a practical procedure for primary amides synthesis; water and tert-butanol are the only by-products. A commercial drug, Piracetam, was prepared in one step with 73% yield as well.
