Piracetam Hydrazide Options

[Isochroma]

Piracetam Hydrazide

On my quest to find Limitless's NZT-48, today I collected some documents about a piracetam derivative that has only been tested on lab animals called Piracetam Hydrazide:

Piracetam Hydrazide
{aka. 2-(2-oxopyrrolidin-1-yl)acetohydrazide}
{aka. 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide}

The terminal NH2 of Piracetam is replaced by NH-NH2 to obtain the hydrazide - though that is not the synthetic route for its production.

thallanylzirconio-methyl-tetrahydro-triazatriphenylene: Real or Fiction?

"Piracetam derivatives with a hydrazide grouping in the side chain
combine nootropic activity and a specific stimulant effect." - Study (see below for details)

What interested me about this compound is not only that it hasn't been tested in humans, but that in rats it prevented hypoxia-instigated brain damage and even death - while piracetam did not. Due to the volume of material, I have bolded the sections of particular interest:

Patent: (2-Oxo-pyrrolidines)-acetic hydrazides (1978)

Description:

"The invention concerns novel (2-oxo-pyrrolidine-1)-acetic hydrazides. These hydrazides and 1,2-bishydrazides, respectively,offer special advantages as starting substances in the preparation of piracetam. These hydrazides also have as such a superior pharmacological effect e.g. as psychopharmacons (nootropic substances).

The substance (2-oxo-pyrrolidine-1)-acetamide has been used recently under the generic name piracetam as a drug against traveling sickness, for the treatment of senile involution (A. J. Stepink, Arzmeimittelforschung 22, 1972, No. 6, p. 975/977) and as a nootropic agent for influencing the learning capacity. (W. Strehl, A. Brosswitz, Therapiewoche 36, 1972, p. 2975). According to J. Charbaut et al (Ann. Med. Psychol. 1, 1973, p. 281/286) an improvement was found only in 45% of geriatricpatients, while 40% showed no improvement.

From German Offenlegungsschrift No. 1,620,608 it is known to prepare (2-oxo-pyrrolidine-1) acetamide from (2-oxo-pyrrolidine-1) acetic ethyl ester by amidation with ammonia. But the products obtained according to this process are very impure andmust be recrystallized repeatedly for purification. This requires not only a considerable technical effort, but also leads to yield losses. Besides, an extreme excess of ammonia is required in this process, namely 10 times more NH.sub.3 than is stoichiometrically required for the reaction. Thus, more than 9 moles of ammonia must be removed per mole (2-oxo-pyrrolidine-1) acetamide and be processed at great costs and/or be removed. Besides, this known process requires considerable amounts of solvent. This complicates the process further and increases the costs. Other disadvantages are present in the known process, e.g. in handling the apparatus and in view of environment protection, resulting from the fact that ammonia is constantly introduced in gaseous form during the reaction.

One object of the invention is to provide compounds and methods for their preparation which have a superior effectiveness as pyschopharmacons. Another object of the invention is to make chemical compounds available which permit simplification of the reaction and in the handling of the apparatus during the reaction to the corresponding acetamides, which avoid at the same time the use of great excesses of reaction components.

These objectives are achieved according to the invention by means of the new (2-oxo-pyrrolidine-1) acetic hydrazides of the formula ##STR1## where R1 denotes a hydrogen atom or a group of the formula ##STR2##

These new hydrazides are obtained by reacting (2-oxo-pyrrolidine-1) acetic esters of the formula ##STR3## where R2 denotes an alkyl group with 1 to 4 C-atoms, with hydrazine or with a hydrazine derivative of formula I, where R1 denotes a hydrogenatom.

In a special embodiment, it is provided in this process that (2-oxo-pyrrolidine-1) acetic ester of formula III is used, where R2 denotes --CH.sub.3 or --C.sub.2 H.sub.5.

A special advantage of this process is that the (2-oxo-pyrrolidine-1) acetic ethyl ester used as a starting substance, for example, can be employed in a technical quality or in crude form, as it is obtained from its method of production. If wewant to use presently known (2-oxo-pyrrolidine-1) acetic esters, we find that these are available only in a very impure form and are difficult and expensive to purify because of their high boiling points. The impurity of these acetic esters is of noimportance in the process according to the invention, because the hydrazide is always formed in a smooth reaction and the hydrazides obtained are very pure.

The reaction of the (2-oxo-pyrrolidine-1) acetic esters of formula III with hydrazine is generally exothermic and therefore begins spontaneously when the components are mixed with each other. The reaction rate depends, among other things, uponthe reactivity of the ester groupings. The temperature of the mixture, which already begins to react at room temperature, for example, can be increased either by developing its own heat of reaction or by supplying external heat. This way the reactionrate is adapted to the reactivity of the components.

The use of (2-oxo-pyrrolidine-1) acetic methyl ester is preferred, because of the reactivity of the ester. But we could also just as well use the ethyl ester, propyl ester, isopropyl ester or the butyl esters.

It is advisable to use additionally for this reaction low alkanols, such as methanol or isopropanol. The use of a solvent permits one to control the reaction more accurately and to regulate the temperature increase up to a certain amount. Theadditional use of a solvent also affects the heat distribution in the reaction mixture, the reaction rate, and, therefore, also the total reaction time. If the temperature of the mixture is increased, after mixing the components (by adding into theester), up to the boiling point of the solvent, this temperature can also be regulated accurately by the selected solvent. Thus, for example, in the reaction with acetic methyl ester in methanol or isopropanol, the heating is continued for several hourswith reflux after the components have been mixed. Subsequently, the desired hydrazide is crystallized from the cold reaction mixture and can be easily isolated, washed with a solvent, and dried at room temperature.

Substantially molar ratios are required for the reaction of the ester of formula III with hydrazine for the formation of the hydrazides, e.g. 1 mole ester per 1 mole hydrazine. Preferably, however, a slight excess of hydrazine is used, e.g., 1.1or 1.2 mole hydrazine per 1 mole ester. In this process the ordinary available technical grade hydrazine hydrate can be used. If solvents are used which contain small amounts of water, and/or hydrazine hydrate, the water is first separated by acetropicdistillation, so that it does not interfere with the reaction.

If less than 1 mole hydrazine is used per mole ester, for example, 0.9 mole hydrazine, this does not result in any disadvantages, despite the theoretical excess of ester in the reaction mixture. With excess ester, the originally formed hydrazineof formula I, where R1 denotes a hydrogen atom, can further react with the ester, forming the hydrazide of formula I, wherein R1 denotes a group of formula II. When both hydrazines are formed this way, side by side, it is not difficult to separate thesetwo substances from each other.

The hydrazide of formula I, where R1 denotes hydrogen, is soluble, for example, in hot methanol or hot isopropanol, but the hydrazide of formula I where R1 denotes a group of formula II is only soluble in hot methanol. This means that onecompound can be separated first with hot isopropanol.

The hydrazide of formula I where R1 denotes a group of formula II, namely 1,2-bis-(2oxo-pyrrolidine-1) acetic hydrazide, is generally formed at elevated temperature (above 50 degrees C., and preferably between 100 degrees and 180 degrees C.), with only small amounts of solvent, or without any solvent, and with a corresponding excess of ester, if we start from hydrazine as the second reaction component, or by direct reaction between the (2-oxo-pyrrolidine-1) acetic hydrazine and the(2-oxo-pyrrolidine-1) acetic ester. If solvents with a higher boiling point are used and in smaller amounts, for example, such as butanols or isopropanol or mixtures thereof, the formation of 1,2-bis-hydrazide can be increased with the corresponding quantitative ratios of the starting substances. The use of small amounts of solvent has the advantage that a crystal sludge is obtained which is suspended in the solvent and which can be easily processed. Besides, (2-oxo-pyrrolidine-1) acetic hydrazide and (2-oxo-pyrrolidine-1) acetic methyl ester can be mixed as starting components without a solvent, heated and the pure 1,2-bis-hydrazide can be obtained by redissolution in methanol.

(2-oxo-pyrrolidine-1) acetic methyl ester is obtained by reacting a (2-oxo-pyrrolidine-1) metal compound of the formula ##STR4## where Me denotes an alkaline metal atom, with monohalogen acetic ester, using a monohalogen acetic methyl ester as amonohalogen acetic ester.

Preferably monochlorine and/or monobromine acetic methyl ester is used. Preferred metal compounds of the above formula IV are (2-oxo-pyrrolidine-1) lithium, (2-oxo-pyrrolidine-1) sodium or (2-oxo-pyrrolidine-1) potassium. The reaction ispreferably carried out in a non-polar or slightly polar organic solvent or in mixtures thereof. Preferred solvents are e.g. benzene, toluene and/or hexane.

The (2-oxo-pyrrolidine-1) acetic methyl ester thus obtained is much more suitable for further reaction on the ester grouping. This methyl ester has a boiling point which is lower by 12.degree. C. than the corresponding ethyl ester; consequentlyit can be purified much more easily and very gently by distillation. This is of particular importance since the pyrrolidine ring can be split by higher thermal stress, so that deep black resinous impurities are formed. Furthermore, the use of theacetic methyl ester results in a better space-time yield in consequent reactions. The acetamide obtained over the corresponding hydrazide or a hydrazide derivative is much purer than that obtained by starting from (2-oxo-pyrrolidine-1) acetic ethylester.

The (2-oxo-pyrrolidine-1) metal compound of formula IV is obtained from pyrrolidine of the formula ##STR5## in an organic solvent with an alkali amide, for example, sodium amide, or with an alkaline metal alkyl, such as butyl-lithium. Instead ofsodium amide or butyl lithium the analogous derivatives of the other alkaline metals or other alkyls can also be used. The (2-oxo-pyrrolidine-1) metal compounds are produced in the known manner. The metal compounds thus obtained need not be isolatedfrom the corresponding solution of the (2-oxo-pyrrolidine-1) metal compounds. Rather, these solutions can be used directly for further reaction with the monohalogen-acetic methyl ester, which is a special advantage of the process of the invention, sinceit permits one to work continuously in the same apparatus. Thus, no yields are lost in the isolation of intermediate products. Of particular advantage also are the low equipment costs.

The (2-oxo-pyrrolidine-1) acetic hydrazides of formula I can be transformed by reduction or hydration into (2-oxo-pyrrolidine-1) acetamide of extremely pure form. For this reaction the hydrazides of formula I can be used, both in the form ofwhere R1 denotes hydrogen, and in the other form where R1 denotes a group of formula II. Mixtures of these two substances can also be used without any disadvantage. Consequently the hydrazides according to the invention, which can be easily isolated ina very pure form, or need not be isolated if they are obtained from a process variant (solvent, temperature, molar ratios etc.) in a mixture.

With the process according to the invention the the hydrazides are obtained in a substantially quantitative yield:

Pharmacological effectiveness

The compounds according to the invention showed a greater nootropic activity in animal tests than piracetam according to the state of the art, and thus they represent an enrichment of the pharmacological field.

For a pharmacological comparison between the compound 1,2-bis-(2-oxo-pyrrolidine-1) acetic hydrazine according to the invention with piracetam we used male rats of 150-200 g weight, which were divided by means of a random table into three groupsof 10 animals each. After we had made sure in a preliminary test that the animals could not find their way to the exit of a water labyrinth within 5 minutes (method based on C. Giurgea et al, Pharmacol. (Paris) 3, 1972, p. 17-30), the groups were exposed before the test proper on four successive days and on the 7th day to a deficit of oxygen, in order to cause brain damage. This was done by introducing nitrogen into a desiccator after displaying the air. The animals remained in the vessel for a sufficient length of time until they assumed a lateral position under anoxemic cramps. 30 minutes before they were introduced into the nitrogen atmosphere each animal of a group was given introperitoneally (i.p.) 100 mg 1,2-bis-(2-oxo-pyrrolidine-1)acetic hydrazide, or 100 mg piracetam or, in the control group, a corresponding volume of a physiological salt solution per kg body weight. On the days when the passage through the water labyrinth was tested, the animals were put into the labyrinth after the nitrogen atmosphere had been removed, and the mistakes which the animals made until they reached the exit and the number of animals which did not find the exit at all within the test period were recorded.

The tests were carried out according to the method of the simple blind tests, that is, the laboratory technician who supervised the tests was not informed as to which animals belonged to which group.

Figure 1

It can be seen from the curves in FIG. 1, the piracetam did not influence the frequency of mistakes in the test animals, that is, control animals and piracetam animals made the same number of mistakes, but those treated with the compound according to the invention made far fewer mistakes. In the evaluation of the curves according to the test, a statistical security with an error probability of less than 5% was found in individual points of the curves.

Figure 2

In FIG. 2 the percentage of animals which had not found the exit of the labyrinth in a given time unit is plotted on the ordinate. In this type of evaluation it could also be shown that piracetam did not influence the behavior of the animals,while more animals of the group tested with the compound according to the invention had reached the exit of the labyrinth.

It should be emphasized that these results were obtained with equal doses of the compound according to the invention and of piracetam, namely 100 mg per kg body weight. Since the molar weights of 1-bis-(2-oxo-pyrrolidine-1) acetic hydrazine and piracetam are in a ratio of 1:2, it could be shown by these tests that the compound according to the invention is twice as effective as piracetam.

In order to further prove the pharmacological superiority of the compound according to the invention over piracetam, rabbits were initially given (2-oxo-pyrrolidine-1) acetic hydrazide and, one hour later, given the sodium salt of 5-ethyl-3-(1-methylbutyl)-barbituric acid to produce artificial intoxication.

Piracetam and (2-oxo-pyrrolidine-1) acetic hydrazide were administered in a dose of 100 mg/kg, one hour before 5-ethyl-5-(1-methylbutyl)-barbituric acid (phenolbarbital-sodium 40 mg/kg i.v.) was given and the following results were obtained: lethality: control (NaCl i.v.) 3/7 = 43%; piracetam 2/5 = 40% (2-oxo-pyrrolidine-1) acetic hydrazide 0/5 = 0%.

It was thus found that the compound according to the invention completely prevented death.

The present invention also comprises pharmaceutical preparations which contain, in addition to non-toxic, inert pharmaceutical carrier substances, the active substance according to the invention, as well as methods for the preparation of thesecompounds.

The present invention also comprises pharmaceutical preparations in dosage units. This means that the preparations are available in the form of individual parts, e.g. tablets, dragees, capsules, pills, whose active substance is a fraction or amultiple of a single dose. The dosing units can contain, for example, 1, 2, 3 or 4 single doses or 1/2, 1/3 or 1/4 of a single dose. A single dose contains preferably the amount of active substance which is administered in one application and whichcorresponds usually to a whole, a half, a third or quarter of a single dose.

By non-toxic, inert pharmaceutically suitable carrier substances we mean solid, semi-solid, or liquid diluents, fillers or formulation aids of any type.

Preferred pharmaceutical preparations are tablets, dragees, capsules, pills, pellets, solutions, suspensions and emulsions, as well as powders.

Tablets, dragees, capsules, pills and pellets can contain the active substance, in addition to the common carrier substances, like fillers and diluents, binders, moisturizers, explosives, solution inhibitors, resorption accelerators, wetting agents, adsorbents, lubricants or mixtures of these substances.

The tablets, dragees, capsules, pills and pellets can be provided with the usual coatings and coverings containing opaquing agents, if necessary.

The active substance can also be contained in microcapsules with one or more of the above indicated carrier substances.

The therapeutically effective compounds should be contained in the above-mentioned pharmaceutical preparations preferably in a concentration of about 0.1 to 99.5%, and preferably 0.5 to 95%, by weight of the total mixture.

The above indicated pharmaceutical preparations can also contain additional pharmaceutically active substances, in addition to the active substance according to the invention.

The above indicated pharmaceutical preparations are produced in the known manner according to known methods, for example, by mixing the active substance(s) with the carrier substance(s).

The present invention also comprises the use of the active substance according to the invention, as well as of pharmaceutical preparations which contain the active substance according to the invention, in human and veterinary medicine to prevent,improve or cure diseases which can occur in the cerebral functional region. These are, for example, chronic brain disfunctions, such as cerebral schlerosis, weakness of memory after circulatory disorders as a result of alcoholism or traumaticexperiences.

In general, it was found expedient to administer the active substance according to the invention in total amounts of about 1.2 to about 2.4 g per 24 hours, if necessary, in the form of several single doses to obtain the desired results. A singledose contains the active substance according to the invention preferably in amounts of about 100 to 500 mg, and preferably, 300 to 400 mg. But, it may be necessary to deviate from the above indicated doses, depending on the type and the body weight of the object to be treated, and on the type and severity of the disease.

The invention will now be described more fully by way of example.

EXAMPLE 1

Preparation of (2-oxo-pyrrolidine-1) acetic hydrazide

Into a solution of 38 g hydrazine in 200 ml isopropanol, 157 g of (1 mole (2-oxo-pyrrolidine-1) acetic methyl ester was added with stirring. The reaction was exothermic; so the addition rate was regulated.

By external influence and by regulating the addition rate, the temperature rises slowly to about 50.degree. C. Then the reaction mixture was heated for another 3 hours with reflux. Subsequently, the reaction mixture was allowed to cool. Fromthe cool reaction mixture the hydrazine crystallized in the form of colorless crystals. The crystal sludge was drained off, washed twice with cold isopropanol and dried at room temperature.

The hydrazide yield was 1429 g (91% of the theoretical); the melting point was 58.degree. C.

The nitrogen determination had the following result:

N-calc. 26.74%. N found 26.87%.

The mother liquor was used again, in unchanged form, in the next batch and the yield increased slightly to 96% of the theoretical.

EXAMPLE 2

Preparation of 1,2-bis-(2-oxo-pyrrolidine-1) acetic hydrazine

A mixture of 157 g (1 mole) of (2-oxo-pyrrolidine-1) acetic hydrazide and 157 g (1 mole) of (2-oxo-pyrrolidine-1) acetic methyl ester was heated for 24 hours under stirring to 150.degree. to 170.degree. C. The reaction mixture was allowed tocool off. After the reaction mixture had cooled to room temperature, it was heated under stirring with reflux in 400 ml methanol, until it completely dissolved.

After cooling the mixture crystallized in colorless crystals which were drained off, washed with isopropanol, and dried at 50.degree. C. The desired hyrazide was obtained in a yield of 234.3 g (83% of the theoretical); the melting point was203.degree. C.

The nitrogen determination had the following result:

N-calc.: 19.85%. N-found: 19.84%.

The mother liquor were used again in unchanged form for several batches and the yields increased to 94%.

EXAMPLE 3

Preparation of (2-oxo-pyrrolidine-1) acetamide

157 g (1mole) of (2-oxo-pyrrolidine-1) acetic hydrazide was dissolved in 400 ml dry methanol and hydrated with 10 g Raney nickel at 20 excess atmospheres in a closed vessel at 100.degree. to 120.degree. C. until hydrogen absorption had stopped. After opening the pressure vessel, the solution was filtered off hot from the catalyst; the catalyst could beused again for a new batch.

The filtrate was concentrated; the still hot concentrate was mixed with 400 ml isopropanol; subsequently the mixture was stirred cold and, after draining and washing with isopropanol, 140 g (2-oxo-pyrrolidine-1) acetamide (89% of the theory) wasobtained in the form of colorless crystals with a melting point of 151.degree. C.

The mother liquor was used again in unchanged form for several batches so that the yield increased to 95%.

The nitrogen determination had the following result:

N-calc.: 19.72%. Found: 19.73%."

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After more searching I finally found a different paper on this novel molecule - this one containing a most thoroughly delicious paragraph which promptly stoked my fantasy of real NZT-48 into a flaming bonfire:

"Piracetam and its 8 derivatives were studied in experiments on mice and rats with the use of standard neurotropic tests and nootropic activity tools. The electrophysiological index of GABA-ergic inhibition (the recovery cycle of cortical evoked potentials) was also investigated. It was shown that piracetam derivatives as well as piracetam itself have a pronounced antihypoxic activity and prevent the amnestic effect of electroshock in experimental passive avoidance. Most of them were inactive according to the standard neurotropic test. Piracetam derivatives with a hydrazide grouping in the side chain combine nootropic activity and a specific stimulant effect, while the derivatives possessing a phenyl ring combine nootropic and depressant activity.": Neuropharmacological properties of piracetam derivatives (1982)

The depth of piracetam with the punch of a stimulant? The world awaits human tests.

The Russians studied the racetams in a very different way from other institutions in other countries. Profit motive distorted by patentability and FDA concerns killed racetam research everywhere else. The Russians had no reasons to stop though... their orientation was purely pragmatic. To achieve the best possible function for applied programs - like their space missions. From that purely pragmatic approach came Phenotropil (Phenylpiracetam). This method - and goal - is the exact opposite of the ridiculously wasteful yet educationally incisive ITER energy program - a scientific gravy-train to nowhere whose only guarantee is that net-energy nuclear fusion will always be twenty-five years away from fruition.

The Russians developed racetams like the Americans developed Apollo. Enough said.

On to the next study: Piracetam Hydrazide boosts immune function:

"Immunomodulatory effects of piracetam and a number of its derivatives were studied in mice. It was shown that multiple injections of such substances at a dose of 50-200 mg/kg change the amount of antibody-forming cells in the spleen of animals immunized with sheep red blood cells. The dose of 200 mg/kg was the most effective one, with the direction of immunomodulatory activity depending on the chemical composition of the compounds. Thus joining of phenol radical to piracetam molecule strengthened immunosuppression, and vice versa insertion of hydrazide group led to stimulation of antibody formation. It is stressed that immunosuppressive effect of piracetam must be taken into consideration during the clinical use of the drug": Effect of piracetam derivatives on antibody formation (1985): the Russians again.

I shall wrap with the sweetest - or perhaps bitterest part - not only is this molecule unregulated, but three suppliers already have it for sale:

Angene: 2-(2-OXOPYRROLIDIN-1-YL)ACETOHYDRAZIDE: RFQ sent by email 2011/07/03

ACC Corporation: 2-(2-OXOPYRROLIDIN-1-YL)ACETOHYDRAZIDE: RFQ sent by email 2011/07/03

Santa Cruz Biotechnology: 2-(2-OXOPYRROLIDIN-1-YL)ACETOHYDRAZIDE: $178 USD / 1g

And for the adventurous a synthesis from UCB Pharma, the inventor of Piracetam:

2-Oxo-1-Pyrrolidine Derivatives, Processes for Preparing Them and Their Uses

9.2. Synthesis of 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide.
In a 250 ml three necked flask fitted with a magnetic stirrer, hydrazine hydrate (5.78 g, 0.18 mol, 3 eq) is added to a solution of 1-[2-(aminooxy)-2-oxoethyl]-4-propylpyrrolidin-2-one (11.99 g, 60.29 mmol) in EtOH (125 ml). The mixture is heated 4 h at reflux, cooled down to room temperature, diluted with brine and extracted with CH2Cl2. The combined organic phases are dried over MgSO4 , filtered and evaporated to afford 11.0 g of 2-(2-oxo-4-propylpyrrolidin-1-yl)acetohydrazide."

Yield: 83%.

LC-MS (MH + ): 200.

To end, NZT-48 is the target so nicely painted in the film and its root work the novel - Illuminating the Dark Fields. It provides an ideal wishlist for the perfect nootropic and the name itself can also be appropriated - or expropriated - when we - or me - discovers a material both potent and powerful enough to take up the name without shame.

When that day comes I will be handing out those magic clear pills and changing lives forever. To that end my next post will be on a very different yet similar subject: the substitution of certain atoms in the Piracetam molecule rather than the addition or subtraction of functional groups, in order to slightly modify the molecule's global electric field rather than produce the often overt, qualitative differences seen after additive functionalization.

Dual rationales lie behind such an approach: first, we're already 90% there with Piracetam itself - and as such only a slight rekeying may be necessary to achieve spectacular increases in both efficiency and efficacy. Second, that the action of Piracetam is not based on chemical reaction but rather the influence of its global electric field on neighboring molecules. For a simple analogy, think of a drop of detergent in water - it does not react with water but by its mere presence modifies the eletronic functions of water molecules within its electropotential reach - drastically changing both the nanoscopic and macroscopic properties of said medium. More on this later.

[lucid_dream]

Second, that the action of Piracetam is not based on chemical reaction but rather the influence of its global electric field on neighboring molecules

this seems premature since the mechanisms underlying piracetam's effects have not been demonstrated. They most assuredly are chemical in nature.

[Isochroma]

I can assure you it is not premature. Both the lack of metabolism and lack of receptor binding support the statement. Recently very weak bindings have been found, but the weakness is such that this phenomenon is more association than 'binding'.

It has also been postulated that piracetam has effects on membrane fluidity, which I am in total agreement with. These effects - like that of detergent in water - occur because piracetam alters the cellular membrane by interspersing itself between the polar heads of fatty acid phospholipids - increasing membrane fluidity. Fish oil also does so because its omega-3 fatty acids are more flexible and thus fluidize the membrane while saturated and trans-fats stiffen the membrane and decrease its permeability.

The main reason Piracetam's mechanism of action remains incompletely elucidated even today is because it is not something easy to quantify like receptor binding or a chemical reaction. Instead, its global electric field influences the molecules nearby and thus alters the biosystem in which it resides. Computational simulation of such large multi-molecule field interactions is far more complex than the simple binding of one molecule with another (aka. receptor interactions) or a chemical reaction. This is because any computational simulation must take into account the sum total of thousands or millions of electric fields in order that the totality behave as it does in reality. Even today's supercomputers are not up to the task.

In contrast, the highly functionalized Piracetam derivatives Aniracetam and Pramiracetam are both metabolized and also - not coincidentally - have highly prominent receptor interactions. Aniracetam is metabolized to anisic acid and p-methoxyhippuric acid. This study shows that only 34.61% of orally administered Pramiracetam was excreted unchanged in dogs 72 hours after a single dose. Considering the short half-life of 2.3-3.9 hours also found in the study, and also considering that Pramiracetam is not stored in fatty tissues - the only logical conclusion is that the remainder - ~65.39% - was metabolized.

Such interactions with mammalian metabolic systems further demonstrate that the highly functionalized Aniracetam and Pramiracetam indeed have chemically reactive 'hooks' and thus are also likely to exhibit stronger, more extensive and particularly de novo receptor interactions that Piracetam and Oxiracetam lack. The functional groups are so named because they literally 'functionalize' an otherwise 'nonfunctional' (aka. not-chemically-reactive) backbone. It's like the dfference between benzene and hexane or alkanes vs. alkenes or alkynes.

Like a tree that has been artificially made to grow in one direction, racetam research has also received a particularly biased mode and directionality of investigation, so the results mirror the ability of researchers to understand within the context of their limited training and the requirements to obtain grants from institutions and approvals from the FDA: new molecules will only be tolerated if they can provide these. Thus the emphasis - to the near total exclusion of alternatives - of piracetam derivative research on receptor-targeted, easily understandable, easily computable and - not unexpectedly - chemically reactive functionalized versions. To this date only one Piracetam derivative defies the expansionistic-functionalistic formula: Oxiracetam, whose single extra oxygen atom modifies its effects in some ways slight and others significant - both quantitatively and qualitatively. Piracetam Hydrazide comes in a close second to Oxiracetam with a net addition of one Nitrogen and one Hydrogen.

I believe the addition of these two atoms gives the hydrazide a running chance at retaining the important small-molecule characteristics of Piracetam with increased potency and perhaps altered quality - as tentatively indicated by at least one study quoted above. Only further testing - especially in humans - will answer these questions definitively.

Piracetam and oxiracetam have also both been proved to not metabolize. Both are excreted entirely unchanged as confirmed by radiolabelling studies. I have the papers if you can't believe my words. The lack of metabolism is itself corroborative because the molecules are teflon-like: they have no electrical 'hooks' that can be easily grabbed and manipulated by any of the biomolecules located in mammals.

The constant pursuit of adding functional groups to create or modify receptor ligation has been a half-mistake, because it has compromised the small-molecule's ability to alter membrane properties - in particular mitochondrial membranes - the restoration of whose function is crucial to correcting the fundamental result of aging-caused brain subfunction and outright dysfunction. The restoration of energy-conversion capacity increases the global function of the entire system without introducing a driving penalty as stimulants do.

The size of the piracetam molecule is just as crucial as its geometric-electric field shape. For anything from the macroscopic to the nanoscopic detergent to the oily lubricant, the particle size allows or prevents interspersion at the correct distances and molar concentrations to have the desired fluidity effects. I am trying to look at the system as a mechanical engineer studying mixed-particle fluid flows, because the pure chemists have already had many decades to pursue their paths to exhaustion.

My path is the one not taken: the questions unanswered, the methods untried.

I will explain further in days to come. Now it's back to manga and research.

[Noopept-Power]

Even if there is no study done in humans I'll be willing to buy some of it if CerebralHealth can synthesize it for a reasonable price. The pyrrolidine ring makes everything safe anyway.

[lucid_dream]

The pyrrolidine ring makes everything safe anyway.

I'm not sure what you mean by this, but if you attach cyanides or mercury to the pyrrolidine ring, it certainly won't be safe.

I would be curious if chemists or pharmacologists have synthesized and systematically studied all (or many) chemical variations on the pyrrolidine ring, and classified or rated the chemicals according to cognitive effects. Does anyone know if this is the case or not, and where this information is located?

[Isochroma]

That information is, thanks to the Government, in the dusty files of private corporations who have no interest in releasing it. In fact, their interest is in keeping the data secret unless they can use it in a patent & product.

[Ralfy]

I had to create this account to say THANK YOU Isochroma. I have read your posts, on this site and others, about nootropics and you have convinced me to start taking piracetam. I received my 500mg powder of Piracetam from SNS four days ago. At first I started with 1 gram and every day I've been increasing my dose by 100mg because I don't really feel the effect yet. I will increase my dose to 3 grams tomorrow. I just want to thank you for your informative and very descriptive posts. Please give me any advice you think I'll need. You're my nootropic sensei!

[Isochroma]

Thanks, Ralfy. Wish you the best of success on Piracetam - the alternatives are far more expensive and the non-racetam alternatives have more side effects and less legality. So let's all hope you can get something from the original :)

PS. Piracetam works much better with high-dose fish oil, as the two share complimentary properties.

Also, do avoid any more than 500mg choline per day, or just use natural sources like egg yolk or meat. Choline overdose has nasty symptoms including depression and lethargy. Many folks who gave up on piracetam due to 'side effects' were actually driven from it by the excessive choline they took with it.

For most individuals no extra choline - beyond a good diet - is needed.

[Ralfy]

I've been on Piracetam for 6 days, still no effect. Today I took 5 grams of this stuff on an empty stomache, no effect... Whats wrong with me?

How can I become a producer of Piracetam?
Any helpful websites?

[Isochroma]

Ralfy, there isn't enough wrong with you. That's the problem. Piracetam normalizes the brain's function and the more damage/aging the more the effects are shown immediately. When teens are given it and take a test a week or two later they score higher but virtually none will consciously notice a difference. They're mostly young and undamaged.

Everyone will still benefit but because you're healthier than some (myself included), the effects will be more subtle and take longer to manifest.

You can also try the other racetams - Oxiracetam is your next best bet for an immediate effect. Aniracetam and Pramiracetam cause sleepiness for most. Try them all if you can afford them.

For Piracetam the manufacturer recommends taking it for at least two weeks before testing or noticing a difference. All racetams are long-term builders so don't panic when it isn't an 'instant pill' like the toxic, addictive caffeine/amphetamines/name-your-poison here.

Piracetam is mostly about support. Taking it means not getting tired when you would otherwise. It's harder to notice not being tired than it is to notice being stimulated. The first is a lighter shadow; the second a brighter light.

That isn't as noticeable as, say, the highly obvious and nasty effects of a stimulant. Effects that tell you in no uncertain terms that you've taken a drug. Piracetam just isn't like that because it doesn't unbalance the brain's functions like stimulants/sedatives/hynotics/psychedelics do. So you have to look at the shadows getting lighter more than the sunlight getting brighter - get what I mean?

Your knight in shining armor is there but he's working in the dark so you can't yet easily see him.

[superman]

I'm sure you saw the movie Limitless. The drug in that movie..NZT. NZT is thallanylzirconio-methyl-tetrahydro-triazatriphenylene. Is that a real, possible medication/chemical compound to produce? I am 35 years old. In my younger years I did a ton of psychedelic drugs. LSD seemed to make me almost super intelligent. Obviously the other effects of long term LSD exposure far outweighs the mental benefits. It seems as if NZT(if it is real) would give that mental boost without the "tripping out" effect from LSD? Do you know of anyone...if it is possible...to make NZT? I would be interested in any info or guidance you may suggest.

Ralfy, there isn't enough wrong with you. That's the problem. Piracetam normalizes the brain's function and the more damage/aging the more the effects are shown immediately. When teens are given it and take a test a week or two later they score higher but virtually none will consciously notice a difference. They're mostly young and undamaged.

Everyone will still benefit but because you're healthier than some (myself included), the effects will be more subtle and take longer to manifest.

You can also try the other racetams - Oxiracetam is your next best bet for an immediate effect. Aniracetam and Pramiracetam cause sleepiness for most. Try them all if you can afford them.

For Piracetam the manufacturer recommends taking it for at least two weeks before testing or noticing a difference. All racetams are long-term builders so don't panic when it isn't an 'instant pill' like the toxic, addictive caffeine/amphetamines/name-your-poison here.

Piracetam is mostly about support. Taking it means not getting tired when you would otherwise. It's harder to notice not being tired than it is to notice being stimulated. The first is a lighter shadow; the second a brighter light.

That isn't as noticeable as, say, the highly obvious and nasty effects of a stimulant. Effects that tell you in no uncertain terms that you've taken a drug. Piracetam just isn't like that because it doesn't unbalance the brain's functions like stimulants/sedatives/hynotics/psychedelics do. So you have to look at the shadows getting lighter more than the sunlight getting brighter - get what I mean?

Your knight in shining armor is there but he's working in the dark so you can't yet easily see him.