Drug Development Research 2:463-474 (1982)

Chemistry and Pharmacology of Nootropics

Bruno J.R. Nicolaus
ISF Institute for Biomedical Research, Trezzano SIN (Milano), ltaly
ABSTRACT Nicolaus, B.J.R.: Chemistry and pharmacology of nootropics. Drug Dev. Res. 2: 463-474,
1982.

The paper discusses the chemistry and pharmacology of the nootropics, reviewing the new chemical entities to recently emerge and in particular the five-membered heterocyclic lactams belonging to the pyrrolidinoneclass, such as piracetam and oxiracetam. These gamma lactams are related to the folded conformation of GABA, which seems to play a role in the uptake mechanisms-that is, in the transport of GABA across the membranes into different nervous tissue elements. The classification of nootropics is discussed, taking into consideration the six main criteria recently suggested, which are: no direct vasoactivity, no change in basic rhythm of EEG activity, blood brain barrier passage, positive metabolic activity in humans and animals, low incidence of side-effects, and objective demonstration of clinivicacy. A critical analysis is made of the various pharmacologicaland biochemical models employed to screen the nootropics, includinga new approach based on the impaired learning rate of spontaneously hypertensive rats with cerebrovascular lesions. The activity of the new GABA-derivative nootropic called oxiracetam is also described and compared with the forerunner of the class, piracetam.
Key words: nootropics, pyrroiidinones, pharmacology, chemistry, memory, aging, GABA, GABOB, cyclic GABA, cycllc GABOB

INTRODUCTION
Almost 10 years have elapsed since the term nootropic was coined [l]; despite this long time, nootropics are still controversial because of a substantial lack of agreement as to appropriate classification [2,8]. Nootropics are claimed to selectively act on the cerebral cortex, being characterized by activator, protective, and function restoring effects on nerve cells in distress [3-71. It has been stated that these effects on the CNS are exerted directly on the cerebral cortex, without mediation of the reticular substance and the rhinencephalon. They do not possess sedative or stimulating effects and do not influence behaviour; in this aspect nootropics substantially differ from the
Received April 22, 1982; accepted June 12, 1982. Address reprint requests to Bruno J.R. Nicolaus, ISF Institute for Biomedical Research, Via Leonard0 Da Vinci 1, 20090 Trezzano S/N (Milano), Italy.

0272-4391/82/0205-0463$03.500 1982 Alan R. Liss, Inc.

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psychotropic agents. Since no activity of this nature has yet been reported for other substances, this may be considered an entirely new class of drugs for which the designation of nootropic agents has been suggested.

DEFINITION CRITERIA OF A NOOTROPIC

Since there was no agreement between pharmacologists themselves nor between pharmacologists and psychiatrists about nootropics, Skondia [8] suggested using a unifying metabolic and molecular approach in which the mode of action would be the common denominator for all types of disciplines and pathologies. According to the above, six still valid criteria have been suggested for defining a nootropic substance and they are as follows [8]: I. No direct vasoactivity A. No vasodilation B. No vasoconstriction II. EEG activity: No change in basic rhythm A. Quantitative EEG: Increased power spectrum (beta 2 and alpha) B. Qualitative EEG: Decreased delta waves and cerebral suffering III. Must pass blood-brain barrier A. Under normal conditions B. Under pathological conditions IV. Must show metatolic activity in: A. Animal brain metabolism 1 . Molecular 2. Physiopathological B. Human brain metabolism (clinical evaluation) 1. A-V differences a. Increased extraction quotients of O2 b. Increased extraction quotients of glucose c. Reduced lactate pyruvate ratio 2. Regional cerebral metabolic rates (rCMR) a. Increased ICMR of O2 b. Increased rCMR of glucose 3. Regional cerebral blood flow: Normalization V. Minimal side effects VI. Clinical trials must be conducted with several rating scales designed to objectify metabolic cerebral improvement.

SITE OF ACTION
It has been stated that the nootropics, without themselves undergoing any change, exert a highly complex action on the cortical cells resulting, among other effects, in an increase of the energy reserve by stimulating the transformation of ADP into ATP, restoring to normal a decreased ATP level (e.g., after hypoxia) [9], and facilitating the physiological transfer of information between the two hemispheres via the corpus callosum [lo]. According to the most recent definition given by Giurgea and Skondia [ 11,121, the nootropics, ranking next to the five classical groups of psychotropics (neuroleptics, antidepressants, anxiolytics, psychostimulants, psychodysleptics) are agents which improve integrative brain mechanisms associated with mental performance (memory, learning, problem solving) by their anabolic effect on the brain cell bioenergetic metabolism (glucose, ATP, proteins, RNA, lipids). Their action is not a matter of short-term central stimulation-as in the case of psychostimulants-but rather of a long-term metabolic facilitation, manifesting itself especially when the nerve cell metabolism is disturbed (hypoxia, intoxication, trauma, etc.).

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At the beginning of the century Sherrington (quoted by Giurgea [13]), coined the concept of integrative activity, defining those central nervous mechanisms which lead from elementary reflexes to the performance of a voluntary movement. According to this concept, elementary reflexes are integrated by means of a central mechanism. A large number of studies conducted in a variety of animal species have demonstrated the effects of many chemicals upon learning ability and memory consolidation, storage, and retrieval. The largest part of the known psychoactive drugs act indirectly upon higher brain integrative activities by interfering with processes such as attention, perception, or motivation. Anticholinergics, barbiturates, and in general all sedatives usually reduce learning efficiency and memory retention. On the contrary, anticholinesterases, stimulants, or convulsant drugs in low dosages usually have a facilitative effect on such processes [13]. It should also be pointed out that substances such as strychnine, picrotoxin, nicotine, pentylenetrazol, physostigmine, caffeine, amphetamine, and others that facilitate experimental learning ability are all CNS stimulants but act by very different mechanisms. Indeed, it has been shown that some of them are able to enhance the rate of RNA synthesis, while others, such as amphetamines, are almost devoid of this effect [13]. Consequently, Giurgea suggested a preferential telencephalic site of action for the nootropics. This still controversial hypothesis enables a unification of the complex and challenging aspects of the nootropics pharmacology. Therefore, learning and memory facilitation by a nonanaleptic drug can be attributed, according to Giurgea, to telencephalon functional activation of higher integrative mechanisms [ 131.

CHEMICAL CLASS AND STRUCTURAL CORRELATIONS

The nootropics are a young class. The main new chemical entities for which nootropic activity has been claimed are five-membered heterocycles, are lactams, belong to the pyrrolidinone class, and are figured out as cyclic GABA-derivatives (Fig. I). Piracetam is the prototype of this class. Oxiracetam is a new cyclic GABOB-derivative and differs from piracetam by the introduction of one hydroxy group in beta position to the carbonyl group and by the presence in the same position of a chiralic center [14] (Fig. 2). Few other chemical entities for which nootropic activity is claimed belong to other chemical classes and have no structural correlation with pyrrolidinones (Fig. 3). In spite of the close structural relationship with GABNGABOB, oxiracetam and piracetam do not interact with GABA receptors. This behavior is based on the following assumptions:
(1) Gamma-lactams are related to the folded conformation of GABA (Fig. 4).

(2) The active conformation of GABA on its postsynaptic receptors is the extended one
[ 15,161.

(3) The folded conformation of GABA seems to play a role in transport mechanism [16,17]. (4) All known products with appreciable affinity for GABA receptors are zwitterions [18]. (5) The analogous 2-pyrrolidinone is inactive on gabaergic mechanisms [ 151. (6) It is unlikely that the cyclic structure is cleaved in the organism with formation of the corresponding open chain amino acid [19].

PHARMACOLOGICAL SCREENING: DESCRIPTION OF SOME EXPERIMENTAL MODELS

The first problem which is encountered when studying nootropics is that regarding the method of pharmacological screening. The ISF Institute for Biomedical Research has been working in this field for quite some time and experience has suggested that the first test to which a new potential nootropic should be subjected is that of the evaluation of its effects on normal behavior of mice according to Irwin [20], exploring the doses of 10, 30, 60, 300 and 1,OOO mg/kg. This test permits the quantification-at least in an empirical way--of the effects on spontaneous motility, motor

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Fig. 2. Oxiracetam: a new GABOB-related nootropic drug.

coordination, muscular tone, presence or absence of tremors, convulsions, and of gross effects on the autonomous nervous system as well as the acute toxicity. It is evident that through this test it is possible to make a certain selection and to exclude many of the substances which do not possess the requirements proposed by Skondia [ 8 ] , thus excluding amphetarninelike stimulants, analeptics, cholinergics, tranquilizers, and also many antiepileptics or depressives and strongly vasoactive substances (which at high doses can also modify behavior).

Chemistry and Pharmacology of Nootropics

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Fig. 4. Two-pyrrolidinone and GABA conformations.

The screening of nootropic substances has so far been approached either by evaluating the ability of animals to learn new information by repeated tests carried out with or without administration of the product, or by evaluating the efficacy of the substance in reducing amnesia induced by drugs or electric convulsive shock. In the former, essentially two tests have been used. The first, suggested by Giurgea [7], considers the learning rate by means of a water maze and observing the number of errors made by the animals in successive sessions in swimming through the maze to reach the exit. In the second test the learning rate is evaluated using the classical pole-climbing test and considering the percentage of animals which learn a conditioned avoidance response in successive sessions of learning. Methods which consider the antagonism of the nootropics toward the amnesizing effect provoked either by maximal electroshock or by hypoxia are also widely used for screening purposes. The mnesic retention is evaluated in these cases by tests of passive avoidance. A box with two compartments, one dark and one illuminated, separated by a closable aperture is commonly used. The floor of the dark part is an electrified grid. The animals which pass instinctively from the illuminated compartment to the dark one are given unavoidable foot shocks and when after 24 hr they are again placed in the same conditions they remain in the illuminated compartment, thus

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demonstrating they have learned of the existence of a situation of danger in the dark compartment of the box. The above-mentioned amnesizing treatments, that is to say electroshock or hypoxia, inhibit this learned behavior. The nootropics are able to antagonize the amnesizing effect. Thus, using the above three experimental models or alternative ones like the Y-maze, it is possible to conduct a varied number of experiments using not only normal animals but also animals with reduced mnesic retention due to:

(1) Aging (rats over 15 months old) ( 2 ) Hypoxia (3) Treatment with inhibitors of protein synthesis (cycloheximide and 8-azaguanine) (4) Treatment with depressive substances such as benzodiazepines and phenothiazines (5) Cerebral edema from glucose overload

In the above experimental conditions the rate of learning or the ability to retain a learnt information cannot obviously be strictly assimilated to human memory and must only be considered as indicative of the reactivity or of the integrity of the upper cerebral functions of animals. There are more complex learning models sometimes described in the literature, using the Skinner box for example, and there is also a very interesting elementary model of learning which is that of the fixation of an experience at the spinal level (21). In brief, this method consists of making a cerebral lesion in rats under anesthesia to provoke an asymmetry of the hind limbs which remains irreversibly fixed if more than 45 minutes are allowed to elapse from the end of the anesthesia before carrying out a section of the spinal cord at the seventh thoracic vertebra. If the spinal cord is instead sectioned 35 minutes after regaining consciousness from the anesthesia, the asymmetry does not remain fixed. The nootropics and protein synthesis stimulants abbreviate this fixation time and 35 minutes are sufficient for maintaining the asymmetry. The remarkable degree of specificity of this test is demonstrated by the fact that protein synthesis inhibitors and electroshock increase the time necessary for spinal fixation and many stimulants or sedatives have no activity at all. The same specificity cannot, however, be ascribed to the protective action toward anoxia (protection from death), because it is known also that substances with a depressive action or anticonvulsant action are effective on this experimental model; in fact they have a protective action toward the convulsions provoked by the hypoxia and also they provoke a slowing down of the cerebral functions with consequent minor request of 02, which has nothing whatsoever to do with a nootropic-type effect. Of appreciable interest is instead the action exerted by the nootropics toward the acute intoxication from barbiturates. This activity may be verified experimentally by electroencephalography in cats or rabbits, controlling the time of recovery of the cerebral electric activity after administration of a dose of barbiturate which provokes cerebral electric silence. It has been observed that the nootropics shorten the time of recovery of the EEG activity and that of reappearance of arousal reactions to acoustic stimuli. A minor frequency of mortality has been noted in animals pretreated with oxiracetam or with piracetam compared to those given only the barbiturate. A cerebral vasodilating action of the nootropics is highly controversial: descriptions of an increase of blood flow at cortical level contrast with descriptions of no effect at all on this parameter. It is most likely that if this effect exists, it is probably very slight. Still on the subject of pharmacological evaluation of the nootropics, an experimental model has recently been proposed which, for its similarity with situations which are encountered clinically, shows to be of considerable interest [22]. It has been observed that spontaneously hypertensive rats given 1% NaCl solution to drink for 14 wk develop not only a marked hypertension but also a cerebral vasculopathy due to the presence of numerous small infarcts visible histologically. Said animals have a learning rate of conditioned responses notably lower than that of rats of the same strain given HzO to drink. The substances with nootropic action are able to increase the learning rate in these animals (Fig. 5 ) .

Chemistry and Pharmacology of Nootropics

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Fig. 5. Rats with cerebrovascular lesions: pole climbing test.

It is unlikely that nootropics are effective on already installed cerebral damage (studies are in progress); a favorable action is more probable on structures which are still able to carry out their functions at least partially. What also differentiates the nootropics from the other psychotropics is their unusual pharmacological profile.

OXIRACETAM (ISF 2522): A NEW MEMBER OF THE NOOTROPICS

A new member of the nootropic family-oxiracetam (ISF 2522tsynthesized in 1974 [14,23-271, seems to have all the requisites of this particular class of CNS-active drugs, for example, its nonactivity in classical pharmacological tests (Fig. 6 ) . Oxiracetam has shown in animal tests where phenomena of learning and memory retention are involved to have an appreciable and specific activity [28]. The experiments were performed with various models of learning and memory. In the pole-climbing test [29], oxiracetam given to rats by intraperitoneal and oral route showed to facilitate and improve the learning of the conditioned reflexes at the dose of 30 mg/kg by both routes. This improvement was seen not only in normal rats, but also in elderly rats and in spontaneously hypertensive rats with irreversible vascular damage [301. Positive results have been seen with oxiracetam also in other tests on memory, this time using the maze technique [7, 431. The performance of all the animals treated with oxiracetam, whether normal or with amnesia induced by diazepam, electroshock, or age, always showed to be better than that of controls not given the drug and the number of errors committed by the oxiracetamtreated rats were fewer. In addition, oxiracetam often showed to be active at doses lower than those used to produce the same effects with piracetam [30]. Another technique, suggested by Giurgea [21], which is employed for evaluating the effects of CNS-active pharmacological agents and is easily reproducible in rats, is that of spinal fixation. Also, here oxiracetam showed to be active at doses lower (30 mg/kg/i.p.) than those of piracetam (100 mg/kg/i.p.) [30]. A new screening approach for nootropics is that proposed recently by Banfi [22], which consists in submitting to the above-mentioned pole climbing and water maze tests rats with impaired

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No effect at dose of Mice behavior orientation motility convulsions: electroshock cardiazol strychnine catalepsis (fraction test) aggression chimney test intestinal motility 3000 mg/kg/os loo0 mg/kg/os

500 mg/kg/os loo0 mg/kg/ip/os 500 mglkglip loo0 mg/kg/os

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heart rate carotid pressure respiration vasomotor reflexes 1 1 1 . Dogs electrocardiogram IV. Guinea pigs bronchospasm induced by: acetylcholine histamine serotonin Fig. 6. Nonactivity of oxiracetam in classical pharmacology tests.

100 mg/kg/iv 200 mg/kg/iv

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100 mg/kg/iv

learning from cerebrovascular lesions induced by drinking 1% saline solution for 14 wk. Administering oxiracetam by oral and by intraperitoneal route to these animals at the 13th week at the dose of 10-30-60 mg/kg/i.p. and 30-60-100 mg/kg/OS showed to significantly improve the brain function [311. No matter how interesting the pharmacological picture may be, it is obvious that some mention must also be made of the other aspects: the toxicological one, for example. As can be seen from Figure 7, oxiracetam is practically atoxic [32]. Also, various in vitro and in vivo biochemical studies have been carried out on oxiracetam comparing it with piracetam tested in parallel or in separate experiments [33,34]. Both products in brain slices from adult rats produce activation of protein synthesis, which is currently conceived as indicating a possible effect on learning and memory. They are both inactive on phosphatidylinositol synthesis and they both stimulate the turnover of lecithin and phosphatidylethanolamine. Oxiracetam compared to piracetam has been shown to increase the activity of brain phospholipases A, and A2 and especially that of phospholipase A,. What is particularly interesting is that oxiracetam, unlike piracetam, inhibits the exchange of phospholipid base; this could mean that it is able to stabilize the structural and functional characteristics of the membrane and could thus be correlated to the fixing of a trace or better of a nervous circuit. Oxiracetam also moderately stimulates cerebral glycolysis and in some cases it increases ATP [35]. As regards the pharmacokinetics, the maximum absorption by oral route of oxiracetam is between 1 to 2 hr with a half-life of 108 min; by intravenous route the half-life is around 50 min. Oxiracetam distributes into all the organs with higher concentrations in the liver and the kidneys

Chemistry and Pharmacology of Nootropics

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Increased excitation and diarrhea in rats at 3000 mg/kg/os

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At high doses slight increase in creatinine,

13 weeks per ip in rats 25-300-1000 mg/kg/day

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bilirubin and gamma globulin in rats and moderate increase in lipids, tryglycerides and total cholesterol in dogs
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26 weeks per 0s in rats 100-500-3000 mg/kg/day

52 weeks per 0s in dogs 100-500-3000mglkglday IV. Teratogenesis 50-500-1500 mg/kg/os in rabbits day 6 to day 18 of gestation V. Peri and post natal toxicity 50-500-3000 mgikglos in rats from day 15 of pregnancy to day 20 after delivery VI. Mutagenesis Salmonella typhimurium Schizosaccharomyces pombe (forward
mutation)

No mortality and no signs of any kind imputable to treatment

No significant alterations in maternal or fetal

parameters
No toxicity

Saccharomyces cerevisiae (gene conversion DNA repair) human fibroblasts (EUE) (unscheduled DNA synthesis)

Non mutagenic

Fig. 7. Toxicological profile of oxiracetam.

and with half-life values similar to those of the plasma with the exception of the brain where the half-life value is around 300 min by 0s and 140 min by i.v. [36]. Metabolic studies have shown that oxiracetam is generally eliminated nonmetabolized. The CNS effects of oxiracetam studied using the so-called quantitative pharmaco-EEG method with univariate and multivariate statistics were able to be discriminated from those of placebo at the level of statistical significance and the effects showed to be dose related and time related [37,38]. The study also included quantitative pharmacopsychology tests (for example, flicker fusion, tapping, reaction time, psychomotor performance, and mental performance) which demonstrated that oxiracetam has some effect on spontaneous memory without having significant effects on simple motor performances and mental vigilance. The task at this point was that of confirming under clinical conditions whether the administration of oxiracetam could improve the brain function in pathological conditions involving mainly the cerebral cortex, for example, in intoxication from alcohol or drugs, cranial traumas and their sequelae, cerebral vascular insufficiency, presenility, or senility. Taking this last indication into particular consideration, it is known that with increasing age, the incidence of psychiatric illness becomes greater. It has been estimated that 25% of elderly

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people suffer from psychiatric symptoms and disabilities and 10%of those over the age of 65 years have some degree of dementia (39). The management of these patients is gaining increasing attention, especially as the life-span lengthens continuously, and many therapeutic attempts, including nootropics, have been undertaken to prevent or to reverse the impairment of the upper mental functions associated with the aging process. Not all patients affected with organic mental deterioration are, however, suitable for nootropic therapy. For instance, it is obvious that in very old patients with advanced degenerative dementia, the impairment of the CNS is no longer reversible and so no pharmacological effect can be expected. A greater chance of success is more likely in less old patients with mild signs of intellectual deterioration, due at least in part to cerebral arteriosclerosis. In this kind of patient, there is still a place for symptomatic improvement which could be provided by nootropic drugs. Thus, a double-blind controlled study was carried out on a group of elderly patients diagnosed as having organic brain syndrome. The results of this trial are reported in this issue [40]. The future of the nootropics, and oxiracetam in particular, now depends on various factors and not least of all on how it is assessed clinically. Whereas for other psychotropic classesanxiolytics, tranquilizers, etc .-there is a large variety of scales designed to evaluate their clinical effects, there is no test or battery of tests which are made-to-measure for the nootropics [41].

CONCLUSIONS
To conclude, it has been seen from the data reported here and elsewhere that oxiracetam is a promising nootropic which has an appreciable neuropharmacological activity in animals which has been confirmed also in humans. Though the product has primarily been tested clinically in organic brain syndromes of the elderly, this does not mean that other indications and other age groups could not benefit from oxiracetam treatment. For example, a pilot trial has also been carried out in alcohol withdrawal states [42] in ten patients with an average age of 49.8 years (only two were over 60). The patients were given 2.4-4.8 glday of oxiracetam by oral route for 2 wk, associated when necessary with chlormethiazole. After only 6 days of treatment, the severest symptoms had completely disappeared in all the patients. No side effects were reported. What is more, oxiracetam has been shown to be two to three times more active in certain tests than the best-known representative of the nootropic class, that is, piracetam. ACKNOWLEDGMENTS Many people have helped to make this article possible, but the author is particularly grateful to S. Banfi and M. Pinza for helpful discussion. Several scientists have contributed to the development of oxiracetam: Special mention should be made of G. Pifferi, R. Pellegata and R. Monguzzi, chemists, and of L. Dorigotti, C. Carpi, and G. Bonardi, pharmacologists. Moreover, the author is indebted to Valeria Rodber and Nadia Peviani for the drafting of the manuscript. Special thanks go to Prof. G. Porcellati, who for many years has helped us with his brilliant mind, as well as to Cristina Meran and Milly Meyer, patient assistants of our work groups. Last but not least the author is indebted to Prof. T. M. Itil for having given him the opportunity to participate in the symposium on nootropics.

REFERENCES
1. Giurgea, C.: Vers une pharmacologie de lactivitk intkgrative du cerveau. Tentative du concept nmtrope

en psychopharmacologie actual. Pharrnacol. 25: 115, 1972. 2. Fink, M.: Contribution to an objective classification of psychoactive drugs. 1 lth C.1.N.P Congress, July 1978, Vienna. 3. Mouravieff-Lesuisse, F. and Giurgea, C.: Influence of electroconvulsive shock on the fixation of an experience at spinal level. Arch. Int. Pharmacodyn. Ther. 183(2): 410, 1970. 4. Giurgea, C., Mouravieff-Lesuisse,F. and Leemans, R.: Correlationselectroacologiquesau cours de Ianoxie oxyprive chez le lapin en respiration libre ou artificielle. Rev. Neurol. (Paris) 122: 484, 1970.

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5 . Giurgea, C., Lefevre, D., Lescrevier, C. and David-Remade, M.: Pharmacological protection against hypoxia induced amnesia in rats. Psychopharmacology (Berlin) 20: 160, 1971.

6. Moyersoons, F. and Giurgea, C.E.: Protective effect of piracetarn in experimental barbiturate intoxication: EEG and behavioural studies. Arch. Int. Pharmacodyn. 210: 38, 1974. 7. Giurgea, C. and Mouravieff-Lesuisse, F.: Effet facilitateur du piracetam sur un apprentissage rep6titif chez le rat. J. Pharmacol. 3: 17, 1972. 8. Skondia, V.: Criteria for clinical development and classification of nootropic drugs. Clin. Ther. 2: 316, 1979. 9. Gobert, J.G.: Genkse dun medicament: le piracetam metabolisation et recherche biochimique. J . Pharm. Belg. 27: 281, 1972. 10. Giurgea, C. and Moyersoons, F.: A GABA related hypothesis on the mechanism of action of the antimotion sickness drugs. Arch. Int. Pharmacodyn. Ther. 188(2): 401, 1970. 11. Giurgea, C.: Differential experimental definition of nootropic drugs. Proc. Symp. Nooanaleptic and Nootropic Drugs, Rome, September 17, 1975, p. 83. 12. Benesova, 0. and Skondia, V.: Criteria for clinical development and classification of nootropic drugs. Symposium on nootropic drugs, Prague, 1979. Activ. Nerv. Suppl. (Praha) 21: 203, 1979. 13. Giurgea, C.: Piracetarn: Nootropic pharmacology of neurointegrative activity. In: Current Developments in Psychopharmacology. Vol. 3, p. 222, 1976, Ed. Essman W.B. and Valzelli L., Spectrum Publ. NY. USA 14. De Angelis, L.: Oxiracetam: Drugs of the Future. 5: 405, 1980. 15. Johnston, G.A.R., Allan, R.D., Kennedy, S.M.E. and Twitchin, B: Systematic study of GABA analogues of restricted conformation. In: GABA Neurotransmitters, ed. by P. JSrogsgaard-Larsen. Copenhagen: Publ. Munksgaard, 1979, p. 149. 16. Krogsgaard-Larsen, P. and Johnston, G.A.R.: Structure activity studies on the inhibition of GABA binding 0 : 1377, 1978. to rat brain membranes by muscimol and related compounds. J. Neurochem. 3 17. Krogsgaard-Larsen, P. and Cristensen, A.V.: GABA agonists and antagonists. Annual Reports in Med. Chem., Chapter 5, 15: 41, 1980, Academic Press. 18. Brehm, L., Krogsgaard-Larsen, P. and Jacobsen, P.: GABA uptake inhibitors and structurally related Pro Drugs. In: GABA Neurotransmitters, ed. by P. Krogsgaard-Larsen. Copenhagen: Publ. Munksgaard, 1979, p. 247. 19. Callery, P.S., Stogniew, M. and Geelhaar, A,: Detection of the in vivo conversion of 2-pyrrolidinone to gamma-aminobutyric acid in mouse brain. Biomed. Mass Spectrom. 6: 23, 1979. 20. Irwin, S .: Comprehensive observational assessment. 1A. A systematic quantitative procedure for assessing the behavior and physiologic state of the mouse. Psychopharmacology (Berlin) 13: 222, 1968. 21. Giurgea, C. and Mouravieff-Lesvisse, F.: Pharmacological studies on an elementary model of learning. The fixation of an experience at spinal level. Part I: Pharmacological reactivity of the spinal cord fixation time. Arch. Int. Pharmacodyn. 191: 279, 1971. 22. Banfi, S., Semeraro, C., Allievi, E., Fonio, W. and Dorigotti, L.: Impaired learning rate of SH rats with cerebrovascular lesions: Effects of oxiracetam (ISF 2522), a new nootropic agent. Int. Symp. Cerebrovasc. Dis., Gardone Riviera, 1981, p. 151. 23. Pifferi, G . , Pinza, M., Banfi, S . and Teza, E.: Cyclic GABA-GABOB analogues potentially active on learning and memory. 5th Int. Symp. Med. Chem., Paris, 1976, abstract no. 058. derivatives potentially 24. Pinza, M., Pellegata, R. and Pifferi, G. : Synthesis of new 4-hydroxy-2-pyrrolidinone active on learning and memory. 6th Int. Meet. Int. SOC.Neurochem., Copenhagen, 1977, p. 369. 25. Pifferi, G. and Pinza, M.: Cyclic GABA-GABOB analogues. I. Synthesis of new 4-hydroxy-2-pyrrolidinone derivatives. II Farmaco, E.S. 32: 602, 1977. 26. Pellegata, R., Pinza, M. and Pifferi, G.: An improved synthesis of gamma, delta and ipsilon lactams. Synthesis 8: 614, 1978. 27. Pinza, M. and Pifferi, G.: Cyclic GABA-GABOB analogues. 11. Synthesis of new 2-0x0 and 2,5 dioxodelta-3-pyrroline derivatives. I1 Farmaco, E.S. 33: 130, 1978. 28. Banfi, S., Cornelli, U. and Carpi, C.: Pharmacological study on learning and memory of a new compound: 4-hydroxy-2-oxo-l-pyrrolidinacetamide, ISF 2522. 6th Int. Meet. Int. Soc. Neurochem., Copenhagen, 1977, p. 366. 29. Cook, L., Weidley, E., Moms, R. and Matiis, P.: Neuropharmacological and behavioral effects of chlorpromazine. J. Pharmacol. Exp. Ther. 113(1): 11, 1953. 30. Banfi, S. and Carpi, C.: Promemoria sulla situazione attuale dello studio di ISF 2522. ISF Internal Report No. 296, 1980.

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31. Banfi, S.: Attiviti di ISF 2522 nella velociti di apprendimento in ratti ipertesi (SHR) portatori di lesioni vascolari cerebrali. ISF Internal Report No. 70, 1980. 32. ISF Internal Toxicological Reports, 1977-1981. 33. Fratini, F., Teza, E., Gaiti, A. and Porcellati, G.: The effect on brain metabolism of 4-hydroxy-2-oxo-lpyrrolidinacetamide. 6th Int. Meet. Int. Soc. Neurochem., Copenhagen, 1977, p. 370. 34. Brunetti, M., Fratini, F., Gaiti, A,, Binaglia, I. and Porcellati, G.: De novo synthesis of phosphatidylcholine and phosphatidylethanolamine and base exchange reactions in the brain of aged rats. 6th Int. Meet. Soc. Neurochem., Copenhagen, 1977, p. 367. 35. Meyer, E. and Carpi, C.: Promemoria sulla situazione attuale dello studio biochimico di ISF 2522. ISF Internal Report No. 301, 1976. 36. Bonardi, G., Pellegatti, M. and Donini, E.: ISF 2522-2I4C: Studi di farmacocinetica e metabolismo nel ratto. ISF Internal Report No. 18, 1979. 37. Itil, T.M. and Menon, G.N.: CNS effects of new drugs for the elderly. World Conf. Clin. Pharmacol. Ther., London, 1980, abstract no. 0065. 38. Itil, T.M., Soldatos, C., Bozak M., Ramadanoglu, E., Dayican, G., Morgan, V. and Menon, G.N.: CNS effects of ISF 2522, a new nootropic (a phase I safety and CNS efficacy study with quantitative pharmacoEEG and pharmacopsychology. Cum. Ther. Res. 26 525, 1979. 39. Shukla, R.B.: The role of the primary care team in the care of the elderly. Practitioner 225: 791, 1981. 40. Itil, T.M., Memon, G., Bozak, M. and Songer, A.: Clinical computer analyzed EEG effects of ISF 2522, a piracetam analog (a double blind controlled trial in patients with organic brain syndrome). 3rd World Congress Biol. Psychiatry, Stockholm, 1981. 41. Gainotti, G., Caltagirone, C. and Miceli, G.: Methodological problems in clinical evaluation of nootropic drugs (the treatment of symptoms of senile involution). Drugs Exp. Clin. Res. 1: 333, 1977. 42. Dencker, S.J.: Pilot trial with ISF 2522 in alcohol withdrawal states. Clin. Eur. 18 88, 1979. 43. Alpem, H.P. and Crabbe, J.C.: Facilitation of the long term storage of memory with strychnine. Science 177: 722, 1972.