Current Pharmaceutical Design, 2002, 8, 125-138 125 Design and Study of -like , Controversial Members of the Problematic Class of Cognition-Enhancing Drugs

Fulvio Gualtieri°*, Dina Manetti°, Maria Novella Romanelli° and Carla Ghelardini^

°Dipartimento di Scienze Farmaceutiche, Universita' di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy

^Dipartimento di Farmacologia Preclinica e Clinica, Universita' di Firenze, Viale Pieraccini 6, I-50139 Firenze, Italy

Abstract- Cognition enhancers are drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies. Development of cognition enhancers is still a difficult task because of complexity of the brain functions, poor predictivity of animal tests and lengthy and expensive clinical trials. After the early serendipitous discovery of first generation cognition enhancers, current research is based on a variety of working hypotheses, derived from the progress of knowledge in the neurobiopathology of cognitive processes.

Among other classes of drugs, piracetam-like cognition enhancers (nootropics) have never reached general acceptance, in spite of their excellent tolerability and safety. In the present review, after a general discussion of the problems connected with the design and development of cognition enhancers, the class is examined in more detail. Reasons for the problems encountered by nootropics, compounds therapeutically available and those in development, their structure activity relationships and mechanisms of action are discussed. Recent developments which hopefully will lead to a revival of the class are reviewed.

INTRODUCTION [3]. An extremely complicated neuronal network in the brain regulates the complex mechanism of learning and memory. Cognitive dysfunction is one of the main symptoms Receptors [4] and channels [5] are the major players in the accompanying ageing, stroke, head injury and interactive framework that eventually produces information neurodegenerative diseases like Alzheimer's disease. acquisition, storage and retrieval and knowledge of their Cognition enhancers can be defined as drugs able to facilitate interplay is limited. attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive Acetylcholine [6], dopamine [7], glutamate [8, 9], functions associated with age and age-related pathologies [1]. histamine [10, 11], neuropeptide [12], and serotonin [13] By definition, this class of drugs improve declining receptors have been reported to play a fundamental role in cognitive functions but do not change the rate of progression cognition. Others like adenosine [14], cannabinoid [15], of neurodegeneration [2]. Obviously, drugs that are catecholamine [16], GABA [17], opioid [18], and sigma [19] neuroprotectant or slow down the progression of the disease seem to be involved but their role is, at the moment, less will very likely improve cognitive functions. The documented. Both -operated and potential-operated overlapping of these properties is frequent and in the ionic channels [20, 21] are also critically involved. literature distinction among the modes of action is usually neglected. A prominent role has been attributed to cholinergic receptors and this has been the bases for the cholinergic One of the major challenges of the third millennium will hypothesis [22], that by some scientists has been judged too be to restore normal brain functions in individuals that suffer reductionist [4]. However, considering the complexity of the from neurodegenerative diseases or from the physiological brain and the number of biological entities involved in decline of brain functions related to ageing. However, cognitive processes [23], singling out any mechanism of cognitive neuropharmacology, which should provide the action will invariably result in a reductionist approach. On theoretical support and a set of reliable assays for the the other hand, since many of the receptors and channels discovery of cognition enhancing drugs, is still in its infancy involved in learning and memory eventually produce modulation of cholinergic receptors [24, 25], a pivotal role of the cholinergic system can hardly be disputed and the controversy regarding the cholinergic hypothesis appears of *Address for correspondence to that author at the Dipartimento di Scienze Farmaceutiche, Universita' di Firenze, Via G. Capponi 9, 50121 Firenze, academic interest. Italy, Tel: 0039-055-2757295, Fax: 0039-055-240776, E-mail: [email protected]

1381-6128/02 $35.00+.00 © 2002 Bentham Science Publishers Ltd. 126 Current Pharmaceutical Design, 2002, Vol. 8, No. 2 Gualtieri et al.

Under these circumstances, it is by no way unexpected drug(s) to submit to the clinical tests. These tests, in turn, that cognition enhancing drugs are at the moment poorly should be able to provide reliable and univocal information defined and the tests to detect their activity are under some on the therapeutic utility of the drug candidates. From this criticism, which slows down the pace of discovery of new point of view, the situation of cognition enhancers is rather molecules in this class of drugs. The fact that cognition unsatisfactory. enhancers may use more than one neuronal mechanism does contribute to the poor definition of the class. Many experimental models are currently available for the preclinical evaluation of agents that affect learning and memory processes [3, 26]. In general, they suffer from poor ASSESSING COGNITION AND COGNI-TION quantitation as, due to their nature, they do not allow an ENHANCERS easy construction of dose-effect curves. Mazes are the traditional tool in assessing cognitive performances in One of the conditions for the design and development of animals and both passive avoidance and active avoidance drugs is the availability of simple, reliable, and inexpensive tasks can be planned. Two behavioral tasks that are preclinical assays that allow rapid identification of the commonly used are passive avoidance [27] and Morris water

O NH2 OH H3CO

H3C CH3 H3CO CH3 O memantine idebenone N

O Br O H CO O 3 O N CH3 H NH

indeloxazine N nicergoline H3C CH3 O O O CH3 N CH N Cl O N 3 O CH 3 O N N

meclofenoxate propentofylline CH3

OH O O CH3 CH HO OH 3 HO NH COOH HO OH OH OH hopantenic acid exifone H N O CH3

bifemelane Fig. (1). First generation cognition enhancers: a selection of marketed drugs. Design and Study of Piracetam-like Nootropics Current Pharmaceutical Design, 2002, Vol. 8, No. 2 127 maze [28]. However, they have met much criticism [4, 5, COGNITION ENHANCING DRUGS 29] and their usefulness for predicting the efficacy of cognition enhancers in humans seems minimal, as many Many compounds have been claimed to be endowed with false positive results have been observed [30]. Nevertheless, cognition enhancing activity [34-37] (reviewed by Froestl since passive avoidance experiments on mice are relatively and Maitre [38], for them the terms metabolic enhancer or simple and rapid, they can be used as a quick screening cerebral have also been used) and few of them method to select compounds for further studies to confirm have reached the market for use in some countries for passive avoidance results. In fact, it seems a general opinion memory disturbances. Their use has been controversial and that conclusions about the cognition enhancing effects of a there is no general consensus on their efficacy in humans: the drug should not rest on the results of one experiment. In case of propentofylline (figure (1)), launched in 1994, may general the battery of tests to assess the cognition enhancing be illustrative. This compound has been recently withdrawn activity of new drugs needs to be improved and, as recently from the Japanese market, following the issue of new pointed out by Eid [5]: "Development of effective treatments guidelines for proof of efficacy of drugs [39] even if for dementia would be considerably aided if the stringency of positive reports on its pharmacological efficacy have preclinical behavioral tests could be improved". Of course continued to appear [40]. On the other hand, compounds like this applies also to cognition enhancers in general. nicergoline (figure (1)), an a 1 and 5-HT1A receptor ligand used since 1972 in Italy and other countries, memantine As far as clinical tests are concerned, the difficulties facing (figure (1)), a non competitive NMDA antagonist that has psycho-pharmacologists are numerous. The task of assessing been used for over ten years in Germany, and idebenone major cognitive functions such as memory, language, (figure (1)), an antioxidant drug discovered and used in attention, orientation and reasoning is by no means simple Japan, are now under trial for Alzheimer's disease and look and a variety of protocols for dementia assessment have been promising [41-43]. In general however, except for a few designed [31, 32]. In addition to global and functional cases, the of these early cognition assessment protocols, ADAS Cog (Alzheimer Disease enhancers is ill-defined or unknown. In other cases (Nafronyl, Assessment Scale Cognition Subscale) is the most suitable Vincamine, Cyclandelate), the nootropic action is indirect, for cognition enhancing drugs and has been the mainstay of being the consequence of cerebral vasodilation. cognitive testing in recent dementia trials [33]. Last but not least, clinical trials to test anti dementia drugs are lengthy In Fig. (1) are reported the structures of some marketed and exceedingly expensive. cognition enhancers, except piracetam and piracetam-like

F

O N N OH S N CH3 N O N H C CH3 3 O sabeluzole vinconate Phase III Phase III

OH O O O N CH3 NH N CH S CH3 3

T-588 dabelotine Phase III Phase III

N N

O

Cl O N O N N N O EXP921 Fig. (2). First generation cognition enhancers: drugs in development. 128 Current Pharmaceutical Design, 2002, Vol. 8, No. 2 Gualtieri et al. compounds that will be considered in detail below, and in compounds able to interfere with amyloid plaques formation Fig. (2) a selection of other related compounds that are still are actively sought and the amyloid hypothesis [53, 54] has in development. They can be considered the first generation flanked the cholinergic hypothesis as a rationale for of cognition enhancers. It must be added that some antidementia drug design. preparations of natural origin such as Ginkgo biloba extracts [44], cerebrolysin [45] and gangliosides [46] are also The effort of the pharmaceutical industry in this field is available and are being studied for treating dementia and impressive and a myriad of new potentially useful cognitive impairment. compounds for cognitive disorders are claimed every year in patent literature, as can be appreciated from the periodic In contrast to previous serendipitous discovery, current survey of Baudy [55]. In Fig. (3) are reported some selected research aims to design and synthesise new compounds, on compounds, acting with different mechanisms, that have the bases of present information about neuropathobiology of been shown to possess cognition enhancing properties: some cognitive processes, following the various hypotheses that of them are in development for this use. have been proposed for cognitive decline: among them, the cholinergic hypothesis of Alzheimer's disease has, so far, produced the most useful compounds [47]. Most studies PIRACETAM-LIKE NOOTROPICS consider ligands of the receptors and channels involved in cognitive processes (see above), but compounds that spare Piracetam properties were disclosed in 1967 [56] and this brain neuromediators and neuropeptides (like stimulated the design and synthesis of a large number of acetylcholinesterase [31], MAO [48] and prolylendopeptidase structurally related molecules that were found to be endowed inhibitors [49]) are also valuable. Even if they belong more with a similar pharmacological profile. This class of to the disease modifying group [2], drugs that maintain and cognition enhancing drugs is often referred to as nootropics restore the health of the brain neuronal network (like and it has been thoroughly reviewed by Gouliaev [57, 58]. antioxidants [50], cyclooxygenase inhibitors [51] and NGF Much like the cognition enhancers of the first generation, inducers [52]) are gaining interest. In this respect, piracetam-like nootropics revert amnesia induced by and other amnesing drugs, electroconvulsive

OCH3 CH3

OCH 3 N N

CH3 O donepezil selegiline AChE inhibitor MAO inhibitor Launched 1999 Launched 1981

H3C O F CH3 HN O N H N CH O N N N 3 H O CONH2 O

posatirelin FK-960 TRH analog Somatostatinergic modulator Phase III Phase II O H N O N O O OH N N N N N H NH O

COOK AIT-082 JTP-4819 NGF inducer Prolyl endopeptidase inhibitor Phase II Phase II Design and Study of Piracetam-like Nootropics Current Pharmaceutical Design, 2002, Vol. 8, No. 2 129

(Fig. 3). contd..... CH3 OCH3

N N

N CH3 S N O CH N 3

CH 3 O H3 CO O

F suritozole Benzodiazepine inverse agonist NMDA modulator Phase I Phase II

N O

Cl N

N O H2 N OCH3 C H 4 9 N

RS 67333 linopirdine + 5-HT4 Agonist K Channel modulator

NH

S N N Cl N H3 C N

N CF3 H N F H

ST-587 MCI-225 Adrenergic agonist 5-HT3 Antagonist Fig. (3). Second generation cognition enhancers. shock and hypoxia with an unknown mechanism. This has [62, 63] and glutamate [64] has been reported. Neuro- been a major problem in accepting them as cognition transmitter modulation could be due to interactions with ion enhancers, even though some of them have been found channels: indeed this has been one of the mechanisms effective in clinical trials [1, 59], show excellent tolerability proposed to rationalise activity of some piracetam-like and safety [60] and, in some countries, have been used or are compounds [65]. As can be deduced from the wealth of data currently in development to treat cognitive disorders (see presented by Gouliaev [58] and from the extensive and Table 1). accurate discussion made in the review, a great deal of different biochemical and behavioural findings have been presented for piracetam-like nootropics, but so far, they have Mechanism of Action been unable to indicate a common molecular mechanism of action. On the other hand, generalisation is made difficult by In general, piracetam-like nootropics show no affinity for the fact that, quite often, piracetam-like nootropics do not the most important central receptors (Ki > 10 mM). A share the same behaviour in many biological assays [66, 67]. modest affinity for muscarinic receptors is shown by (Ki = 4.4 mM [58]) and nebracetam (Ki = 6.3 Nevertheless, attempts to find common properties in the mM [61]). Nefiracetam is the only one showing affinity in the class have been made. On the basis of the finding that nanomolar range (Ki = 8.5 nM on the GABAA receptor memory enhancing effects are steroid-sensitive [68], [58]). As a consequence, they do not seem to act on any Mondadori has proposed that nootropics exert a modulatory well-characterised receptor system, although modulation of action on protein synthesis [69]. Protein kinase C (PKC) most central neurotransmitters, in particular acetylcholine activation as well, could be a general mechanism of action of 130 Current Pharmaceutical Design, 2002, Vol. 8, No. 2 Gualtieri et al.

Table 1. Piracetam-like Cognition Enhancers (Nootropics): Drugs Available or in Development

Drug Drug codes Company Year of launch/ phase

Piracetam UCB-6215 UCB 1973

Oxiracetam ISF-2522 ISF 1987

Aniracetam Ro-13-5057 Roche 1993

Pramiracetam CI-879 Warner-lambert 1993

Nebracetam WEB1881FU Boehringer Ing. Awaiting approval

Nefiracetam DM-9384 Daiichi Seyaku Awaiting approval

Fasoracetam NS-105/LAM-105 Nippon Shinyaku Phase III cognition enhancing compounds, as appears from studies on compounds that have been used or studied in more detail, [70], aniracetam [71], and nefiracetam [72]. Very starting from previous reviews [34-38], in particular that of recently, based on the effect of piracetam on the fluidity of Gouliaev and coworkers [57, 58]. mouse brain membranes, Muller and co-workers have proposed that cognition enhancing properties of piracetam a- N-Side Chain Homologues can be explained by their effect on brain membrane properties, in particular by modification of membrane-located From the several a -substituted derivatives of piracetam mechanisms of central signal transduction [73]. However, synthesised (see Gouliaev [57] and the tables available as none of these hypotheses have, so far, gathered general Addendum), etiracetam has emerged as the most interesting consensus. compound. It shows nootropic activity and its S enantiomer, (Fig. (4), also known as UCB L059(S)), which It can be concluded that, thirty years after the is responsible of nootropic activity as well (the R enantiomer identification of piracetam, a unifying hypothesis on the is inactive [58]) has been approved for the treatment of mechanism of action is still lacking and that this class of epilepsy. Apparently, simple alkylation of the side chain cognition enhancers, despite chemical similarity and close results in a definitely different pharmacological and clinical pharmacological profile, uses an amazing variety of profile [76]. However, in line with the odd behaviour of the molecular mechanisms to produce the final nootropic effect. compounds of this series, analogous to mechanism of nootropic activity, that of antiepileptic activity, has not been clearly established. Structure-activity relationships b- N-Substituted Amides The lack of a common mechanism at a molecular level allows sound structure-activity correlations only with in vivo Early efforts to modulate activity of piracetam regarded behavioural assays, which has frustrating consequences on the substitution with different groups of the amide nitrogen. drug design. In fact, the resulting activity is the consequence A large array of substituents has been used and hundreds of of both pharmacokinetic and pharmacodynamic properties compounds of this kind have been synthesised. Most of that may be differently affected by structural modifications. them have been claimed to be active as nootropics, but few Moreover, since the protocols for behavioural tasks that are have survived the preclinical stage [35, 57]. commonly used vary widely between investigators [5], making general comparison of the results difficult, and the Pramiracetam (Fig. (4) [77]) was introduced in 1993. structures studied are fairly heterogeneous, one might wonder The drug has been shown to enhance cholinergic whether SAR's are meaningful at all. This fact, severely neurotransmission in brain pathways involved in cognitive limits the significance of the models of the pharmacophore processes (mainly increasing high affinity choline uptake), to that have been proposed for piracetam-like compounds [74, interact with steroids and to inhibit (Ki = 11 mM) prolyl 75]. However, most of the compounds containing a 2- endopeptidases [58]. oxopyrrolidine structure do present nootropic activity, Nefiracetam (chart (1)) is awaiting approval. It presents a suggesting that this feature plays a critical role in nootropic variety of pharmacological actions as it is reported to activate activity. the cholinergic, GABAergic and other monaminergic systems and to modulate N-type calcium channels [78-81]. It In Fig. (4), the chemical evolution of piracetam-like has proven effective also on b-amyloid induced learning compounds is shown through some of the most studied and impairment [82]. There are indications that these effects may interesting members of the class: except for sunifiram, all be due to activation of protein kinases A and C (PKA/PKC) contain a 2-oxopyrrolidine ring. The following is a short followed by modulation of presynaptic nicotinic receptors discussion on structure and pharmacological properties of the [80, 83, 84]. Design and Study of Piracetam-like Nootropics Current Pharmaceutical Design, 2002, Vol. 8, No. 2 131

O O N CH3 H O N N NH2 H H3C N O N O levetiracetam CH3 O N CH3

sunifiram H3C CH3 O pramiracetam OH N

O O N N N O S NH2 NH2 O F O O unifiram oxiracetam piracetam

O N O N N H O NH2 O fasoracetam O N

OCH3 aniracetam

nebracetam

Fig. (4). Chemical evolution of piracetam-like nootropics.

Another derivative of this type, SNK-882 (chart (1)) [85], Several derivatives of piracetam were obtained by is undergoing phase II clinical trials as cognition enhancing simultaneous substitution in the ring and at the amide drug [86]. nitrogen [57, 58]. One of them, (1, chart (1)) a pramiracetam derivative, has been recently reported in a patent to be active,

CF3 O O O N CH N N 3 H H H N N CH3 N O O O N CH3 H3C N CH3

nefiracetam SNK 882 H3C 1 CH3

Chart 1. 132 Current Pharmaceutical Design, 2002, Vol. 8, No. 2 Gualtieri et al.

O O O O O N N N N

O O O N 1-BCP CX 516 CX 614

Chart 2. thus showing that the pyrrole ring can be substituted been cleaved, maintains nootropic properties, although with without loss of nootropic activity [87]. lower [93, 94]. Aniracetam has been found to have an extremely rapid onset and washout, which is desirable, c- Ring Substituted Derivatives but, on the other hand, it works only at high concentration and is hydrolyzed to anisoyl-GABA to a very large extent Only oxiracetam (Fig. (4)) among the numerous when administered peripherally. To improve the properties synthesised and studied ring-subtituted analogues of of aniracetam, a series of benzoylpiperidines (1-BCP and piracetam [57, 58] survived preliminary and clinical tests CX516), benzoylpyrrolidines and policyclic related and was introduced in 1987. It is used as a racemate. It is derivatives (CX614), that also act as positive allosteric interesting to notice that, also for oxiracetam, PKC seem modulators of AMPA and are often referred to as ampakines involved in the action at molecular level [88]. (chart (2)) [95-97], have been designed. This class of compounds represents one of the most significant results of More recently, N-acylderivatives of 4-phenyl-2- piracetam-like compounds and the drug labeled CX516 is, at oxopyrrolidine endowed with nootropic activity have been present, in phase III development as cognition enhancer [98]. reported [89]. Another member of this family, BMY-21502 (chart (3)) d- N-Side Chain Modified Derivatives [99], has entered clinical trials but, while generally well tolerated, was not significantly superior to placebo in The original acetamido side chain of piracetam can be improving patient conditions [100]. modified without loss of nootropic action and a variety of substituents have been inserted on the pirrole nitrogen, some Nebracetam (Fig. (4)), which is waiting approval, times with a contemporary introduction of a substituent in presents a quite new structure and has direct cholinomimetic the pyrrole ring [38, 57]. properties as it shows some affinity for muscarinic receptors [61]. However, other neurotransmitter systems, like Aniracetam (Fig. (4)), introduced in 1993, is one of the adrenergic [101] and triptaminergic [102], seem involved. most studied. It has been reported to be a potent modulator The enantioselectivity of nebracetam enantiomers has been of the glutamatergic (AMPA) and cholinergics systems and studied. It was found that both isomers increase the release of to block the N-type calcium current [90]. The serotoninergic acetylcholine, the (-) enantiomer being slightly more potent system also seems involved [91]. Action on AMPA [103]. receptor, where it seems to act as a positive allosteric modulator, has been confirmed recently by its high potency Ru-47067 (chart (3)) [104] is a member of a series of in the kinurenate test [92]. Its main metabolite, N-anysoyl- compounds where a sulfonyl group replaces the carbonyl g-aminobutiryc acid, where the 2-pyrrolidinone ring has group of piracetam. However, although they have been

O N N CH3 CF3 O O N O CH3 N CH3 O N O S N O N O CF3 H3C N CF3 Cl

BMY-21502 RU-47067 2 3

Chart 3. Design and Study of Piracetam-like Nootropics Current Pharmaceutical Design, 2002, Vol. 8, No. 2 133

OCH3 S

O N O N H O O COOH N H pidotimod rolipram Chart 4. studied for some time [38, 58], this kind of compound The only compound that has been studied in some detail apparently did not reach clinical development. They are of is tenilsetam (chart (5)) [114], where the pyrrolidinone has interest since sulfonamido function appears also in some formally been enlarged into a piperazinone ring. Its nootropic new, potent nootropic drugs. properties (similar to that of piracetam) seem related to inhibition of protein glycosylation [115]. Two compounds, 2 and 3 (chart (3)), also modified at the N-side chain, have been claimed in patents [105, 106] but no More recently, two other series of products, 4 [116] and 5 other information is available. [117] (chart (5)), have been reported, but no details on their activity are available. e- N-Unsubstituted, Pyrrole Substituted Deri-vatives g- Policyclic Derivatives This kind of compound lacks the N-side chain which is a common feature of piracetam-like compounds. Their Although a few policyclic derivatives of piracetam-like nootropic action demonstrates that this is not a stringent compounds (exemplified by 6 and 7, chart (6)) have been requirement for activity, as was believed for some time. In reported [35], only rolziracetam has been studied in some general, the compounds of this group are derivatives of details reaching phase II clinical studies [118]. pyroglutamic acid. The series of dihydro-1H-pyrrolo[1,2-a]imidazole- Fasoracetam (Fig. (4)), which is currently in phase III 2,5(3H,6H)-diones, with the general structure 8 (chart (6)), trials, is the most studied representative. Fasoracetam has been synthesised and some compounds have been significantly increased cAMP accumulation in membranes reported to be endowed with potent nootropic activity [119]. pretreated with pertussis toxin, indicating that it activates both inhibitory and stimulatory G proteins [107]. This effect Pyrrolidinone compounds condensed with an aromatic seems to be mediated by GABAB receptors, but even ring, as represented by linopirdine (Fig. (3)) or compound cholinergic [108] and metabotropic glutamate [109] receptors T-82 (a donepezil analog [120], chart (6)), do show have been found involved. No information is available on the nootropic activity but, very likely, their pharmacological influence of stereochemistry on nootropic activity of profile is not related to the pyrrolidinone moiety. fasoracetam. Recently, a series of 1,4-diazabicyclo[4.3.0] nonan-9- To this group belong two compounds that, although ones, showing unprecedented potency on mouse passive endowed with some nootropic activity, are used or in avoidance tests, has been disclosed [121]. Among the development for other purposes. Pidotimod (chart (4)) [110] compounds studied, DM 232 (unifiram, see Fig. (4)) is the has been used since 1993 as immunomodulator and rolipram most potent, being able to revert amnesia induced by (chart (4)) [111], a potent inhibitor of PDE IV, is in scopolamine at the minimal active dose of 0.001 mg/kg. development as antidepressant. Interestingly, molecular simplification of the structure of 1,4- diazabicyclo[4.3.0]nonan-9-ones to seco derivatives like DM f- Ring-Modified Derivatives 235 (sunifiram, Fig. (4)) [122], maintained activity and potency, thus suggesting that the pyrrolidinone ring can be Several attempts to modulate nootropic activity through mimicked, at least in this series, by a suitable alkanoic acid manipulation of the pyrrolidinone ring have been reported amide. To the best of our knowledge, there is only one [35, 38, 58, 112, 113]. poorly characterised example of a piracetam-like nootropic

O O R4 CH3 H CH3 N R1 S O O N N R2

N O R3 H (CH2)n-COOR Tenilsetam 4 5 Chart 5. 134 Current Pharmaceutical Design, 2002, Vol. 8, No. 2 Gualtieri et al.

O O O N O N O N H3C O HN CH3 N NH2 CH3 7 rolziracetam 6 H3C

R H3C R2 O N O O

N ( )n N N R1 N O

8 T-82

Chart 6. where a similar situation can be found: aloracetam (chart (7)) diphenhydramine (antihistaminic), baclofen (GABAB [101]. On the other hand, sunifiram, being a benzoylamide, agonist) and clonidine (a 2 agonist) with a potency pattern can be also related to the aniracetam-derived ampakines similar to that reported for scopolamine. Moreover, they mentioned before, which would suggest a similar mechanism were active as well in a test (social learning) where there is of action. no deficit in the cognitive functions.

Unifiram and sunifiram were able to revert amnesia Both unifiram and sunifiram where able to increase the induced by a variety of amnesing drugs suh as release of acetylcholine in the cerebral cortex of freely moving

Fig. (5). Dose-response curve for sunifiram (open symbols) and unifiram (closed symbols) on ACh release from rat cerebral cortex. Compounds were injected ip after 60 min as shown by the arrow. All values are expressed as changes over basal output Vertical lines give S.E.M. Each point represents the mean of 3 experiments. Open squares: sunifiram 0.01 mg/kg; open circles: sunifiram 1 mg/kg; closed circles: unifiram 0.01 mg/kg; closed squares: unifiram 1 mg/kg. Design and Study of Piracetam-like Nootropics Current Pharmaceutical Design, 2002, Vol. 8, No. 2 135 help in restoring impaired cognitive functions, both directly CHO or through the cure of the pathologies that produce cognitive

H3C dysfunction.

N Among other classes of cognition enhancers, piracetam- CH3 like compounds suffer from the lack of a common, generally CH3 accepted, mechanism of action; a condition which has O N precluded, so far, a wide acceptance of these drugs as useful H medicines. Ironically, the very low toxicity of this class of compounds is itself a problem, since it has been considered aloracetam the result of insufficient activity, even if they are active in most preclinical assays and, at least in some clinical trials, their therapeutic efficacy has been found significant. As a consequence, after a period of intense research in the late Chart 7. eighties, interest for this class of drugs has vanished. Nevertheless, research in this field has allowed identification rats (Fig. (5)) showing that, although the compounds lack of two new classes of drugs, the ampakines and affinity for cholinergic receptors, they can modulate the diacylpiperazines, whose cognition enhancing properties cholinergic system. However, the molecular mechanism by look promising. It is hoped that the new recently disclosed which acetylcholine is released is not currently known, even compounds, that seem to be endowed with unprecedented if there are strong indications that a specific target is high potency, will contribute to elucidate the mechanism of involved. action of the class and its revival.

O O CH3 H3C O H 3C O

N N N N CH3

N N N CH3 N O O O O S S S S O O O O

F F F F DM232 9 10 11 Minimal Effective Dose (MED) mg/kg sc 0.001 0.01 0.1 1.0 Fig. (6).

In fact, as shown in Fig. (6), where the minimal effective REFERENCES doses on scopolamine induced amnesia of unifiram and its seco derivatives 9-11 are reported, there is a strict correlation [1] Parnetti, L.; Senin, U.; Mecocci, P. Drugs, 1997, 53, between potency and structural and conformational 752. characteristics of the molecules. [2] Hirai, S. Alz. Dis. Ass. Dis., 2000, 14, S11.

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