2-Pyrrolidinone Moiety Is Not Critical for the Cognition-Enhancing Activity of Piracetam-Like Drugs
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Il Farmaco 58 (2003) 715Á/722 www.elsevier.com/locate/farmac 2-Pyrrolidinone moiety is not critical for the cognition-enhancing activity of piracetam-like drugs Serena Scapecchi a,*, Cecilia Martelli a, Carla Ghelardini b, Luca Guandalini a, Elisabetta Martini a, Fulvio Gualtieri a a Dipartimento di Scienze Farmaceutiche, Universita` di Firenze, Via G. Capponi 9, I-50121 Firenze, Italy b Dipartimento di Farmacologia Preclinica e Clinica, Universita` di Firenze, Viale G. Pieraccini 6, I-50139 Firenze, Italy Received 13 November 2002; accepted 29 December 2002 Abstract Following the indications of previous work, 2-pyrrolidinone moiety of piracetam and piracetam-like compounds has been opened to the corresponding amide derivatives. As found previously in the case of 1,4-diazabicyclo[4.3.0]nonan-9-one compounds, the cognition-enhancing activity of 2-pyrrolidinone compounds is maintained in most cases, suggesting that this moiety is not crucial for activity. # 2003 E´ ditions scientifiques et me´dicales Elsevier SAS. All rights reserved. Keywords: 2-Pyrrolidinone; Moiety; Cognition-enhancing activity; Piracetam-like drugs 1. Introduction This has been a major problem in accepting them as cognition enhancers, even though some of them have Cognitive properties of piracetam were disclosed in been found effective in clinical trials [11,12] and show 1967 [1] and after that a number of structurally related excellent tolerability and safety [13].Nevertheless, a few molecules were found to be endowed with a similar have been introduced in therapy (piracetam, oxiracetam, pharmacological profile. This class of cognition-enhan- aniracetam and pramiracetam) and others are currently cing drugs is often referred to as nootropics and it has in development to treat cognitive disorders (nebracetam, been thoroughly reviewed [2Á/5]. nefiracetam and fasoracetam) [5]. Piracetam-like nootropics revert amnesia induced by The lack of a common mechanism at a molecular level scopolamine and other amnesing drugs, electroconvul- allows sound structureÁ/activity correlations only with in sive shock and hypoxia with an unknown mechanism. In vivobehavioural assays, leading to frustrating conse- general, they show no affinity for the most important quences in drug design. In fact, the resulting activity is central receptors (Ka/10 mM), but are able to mod- the consequence of both pharmacokinetic and pharma- ulate the action of most central neurotransmitters, in codynamic properties that may be differently affected by particular acetylcholine [6,7] and glutamate [8]. A great structural modifications. Moreover, the protocols for deal of different biochemical and behavioural findings behavioural tasks that are commonly used vary widely have been presented for piracetam-like nootropics, but between investigators [14], making general comparison so far, they have been unable to indicate a common of the results difficult. This fact limits the significance of molecular mechanism of action. On the other hand, the models of the pharmacophore that has been generalisation is made difficult by the fact that, quite proposed for piracetam-like compounds [15]. However, often, piracetam-like nootropics do not share the same most of the compounds containing a 2-oxopyrrolidine behaviour on many biological assays [9,10]. structure do present cognition-enhancing activity, sug- gesting that this feature plays a critical role. * Corresponding author. Recently, we have described a new class of com- E-mail address: [email protected] (S. Scapecchi). pounds with a 1,4-diazabicyclo[4.3.0]nonan-9-one struc- 0014-827X/03/$ - see front matter # 2003 E´ ditions scientifiques et me´dicales Elsevier SAS. All rights reserved. doi:10.1016/S0014-827X(03)00111-3 716 S. Scapecchi et al. / Il Farmaco 58 (2003) 715Á/722 Plate 1. ture [16] (Plate 1A) that showed a very potent cognition- and pramiracetam), 4Á/5 (nebracetam and fasoracetam) enhancing activity on mouse-passive-avoidance assay. or both (nebracetam and aniracetam) of the pyrrole High activity was maintained when the pyrrolidinone nucleus. Formally, in the first case, cleavage would ring present in this class of compounds was opened to produce a butyrylamide. However, since we found [17] give the corresponding piperazine derivatives [17] (Plate that increasing the acyl chain produced less potent and 1B), suggesting that in this class of compounds 2- less soluble compounds, we have limited the choice to oxopyrrolidine moiety is not critical for pharmacologi- acetyl and propionyl derivatives. cal action. The compounds studied and their relationships with Continuing our work in this field, we started research the parent drug are indicated in Plate 1. To the best of to verify if these findings applied also to other pirace- our knowledge, there is only one poorly characterised tam-like compounds. Therefore, we have chosen some example of a piracetam-like nootropic where the pyrro- of the most widely used and studied compounds of this lidinone nucleus has been opened in a similar way: class and have prepared and studied their seco deriva- aloracetam [5,18]. On the other hand, it is well known tives, i.e., the analogues where the pyrrolidinone nucleus that aniracetam’s main metabolite, 4-(anysoylamino)bu- has been opened at the level of bonds 1Á/5 (piracetam tyric acid, maintains nootropic properties, although S. Scapecchi et al. / Il Farmaco 58 (2003) 715Á/722 717 with lower potency [19,20]. However, in this case the cleavage of the pyrrolidinone ring occurred at a different site. 2. Chemistry Compound 1 is commercially available. Compounds 2, 3, as well as 11, were synthesised, as reported in Scheme 1, by amidation of the methyl ester of propio- nylaminoacetic acid 12, obtained from glycine methyl ester and propionic acid anhydride, following the Scheme 2. procedure described by Applewhite and Nieman [21] for a similar compound. 3. Pharmacology Compounds 4Á/7 were obtained as reported in Scheme 2. Of them, 4 [22] and 5 [23] have been previously The compounds studied were tested as cognition described, while 6 and 7 were obtained starting from enhancers in the mouse-passive-avoidance test of Jarvik commercially available 4-methoxybenzamide and 4- and Kopp [27], slightly modified by us (see Section 5). In methoxy-N-methylbenzamide [22], respectively. short, mice receive a punishment when entering a dark Compounds 8 and 9 were obtained as reported in room in the training session and remember it in the Scheme 3. 4-Amino-N-benzylbutyramide (8) was ob- session on the following day, unless their memory is tained from benzyl-pyrrolidin-2-ylidene-amine (16) [24]. impaired by the amnesic drug. The parameter measured However, under the conditions (H2O, room tempera- is the entry latency time (expressed in seconds) occurring ture) reported in the literature [25], hydrolysis did not between the time the mouse is placed in the light and the occur and 1 equiv. of NaOH at 80 8C was necessary to time it enters the dark room. On the first day, there is obtain the final product. Compound 9 was obtained the training session, while on the second day the mice from compound 15, obtained from g-butyrolactone and are placed again in the light and the new latency time is benzylmethylamine, through standard methods. measured on animals treated or untreated with the Finally, compound 10 was obtained starting from nootropic drug. Investigated drugs were injected, in a 1Á/ acetylglycine and piperidine according to the literature 10 dilution sequence, 20 min before the training session, [26]. while amnesic drug was injected immediately after Scheme 1. 718 S. Scapecchi et al. / Il Farmaco 58 (2003) 715Á/722 Scheme 3. termination of the training session. Scopolamine hydro- less potent, but compound 11, when given p.o., main- bromide (i.p. 1.5 mg/kg) was used as amnesic drug and tains most of the potency of the parent drug, thus piracetam, pramiracetam, aniracetam, nebracetam and showing a remarkable potency (1 mg/kg) when given i.p. fasoracetam as reference drugs. Comparison of the Also in the case of the derivatives of aniracetam, we latency times of saline-treated animals with those of obtained mixed results: compounds 6 and 7 are less mice that received both scopolamine and the investi- potent, while compounds 4 and 5 are more potent than gated drug gives a measure of the cognition activity of the parent drug. Particularly interesting is compound 4, the compounds tested. As a rule the compounds were which is active at doses of 1 mg/kg i.p. and 3 mg/kg p.o., injected intraperitoneally (i.p.), however, to compare the some 30 times lower than that of the parent compound. data with the literature some of them have also been Both derivatives of piracetam maintain the nootropic administered per os (p.o.). The highest active doses of activity on passive-avoidance test, while 2 is equipotent the investigated compounds did not altered animals’ with piracetam, compound 1 is quite more potent being gross behaviour and were devoid of any behavioural active at the dose of 1 mg/kg i.p. side effect, as demonstrated by Irwing test [28]. In general, as was found in the simplification of 1,4- diazabicyclo[4.3.0]nonan-9-ones [16] to the correspond- ing piperazine derivatives [17],even for the classical 4. Results and discussion piracetam-like nootropics the cleavage of 2-pyrrolidi- none ring is not critical for the nootropic activity. As a The results obtained performing the mouse-passive- avoidance test are reported in Table 1, in comparison matter of fact, in the seco derivatives, in most cases the with the results obtained with the parent compounds. potency of the parent compounds is maintained or even Since some of the reference compounds were quite improved. insoluble in physiological solution, they were given per As regards 2-pyrrolidinone bond that is cleaved, two os (p.o.). When necessary, new compounds have also of the most potent compounds (1 and 4) derived from been tested in this way to make a comparison possible.