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Synthesis and amnesia-reversal activity of a series of 7- and 5-membered 3-acylamino lactams
Abstract
A series of 3-(acylamino)-epsilon-caprolactams and 3-(acylamino)-2-pyrrolidinones was synthesized. Some of these compounds reversed at different degrees electroconvulsive shock- and Scopolamine-induced amnesia, using a step-through passive avoidance in mice. Classical nootropic drugs, i.e., Aniracetam, Oxiracetam, and Piracetam, were used as reference compounds. Within the analyses of data performed, we introduced a new parameter, the confrontation index (CI), which is a function of Mann-Whitney's U statistic. The CI permits a common scale of activity of substances to be generated, independently of probabilistic hypotheses, with higher scores representing higher activities. The most active compounds were characterized by the formylamino and [3-(trifluoromethyl)benzoyl]amino groups in the 3-position of the ring. None of the substances assayed showed any effect on spontaneous behavior and neurovegetative system.
Nitric oxide (NO) mimetics and other agents capable of enhancing NO/cGMP signaling have demonstrated efficacy as potential therapies for Alzheimer’s disease. A group of thiol-dependent NO mimetics known as furoxans may be designed to exhibit attenuated reactivity to provide slow onset NO effects. The present study describes the design, synthesis, and evaluation of a furoxan library resulting in the identification of a prototype furoxan, 5a, which was profiled for use in the CNS. 5a demonstrated negligible reactivity toward generic cellular thiols under physiological conditions. Nonetheless, cGMP dependent neuroprotection was observed. 5a (20 mg/kg) reversed cholinergic memory deficits in a mouse model of passive avoidance fear memory. Importantly, 5a can be prepared as a pharmaceutically acceptable salt and is observed in the brain 12 hr after oral administration, suggesting potential for daily dosing and excellent metabolic stability. Continued investigation into furoxans as attenuated NO mimetics for the CNS is warranted.
α-Amino γ-lactams have been synthesized from carbohydrate derived cyclopropanecarboxylates using N-iodosuccinimide (NIS) and NaN3. Cyclopropane ring opening with NIS and NaN3 in different solvents has been studied. Reductive cyclization of the intermediate di-azides leads to the carbohydrate fused α-amino γ-lactam and γ-lactams. Additionally, the methodology has been successfully extended to the synthesis of a glycopeptide.
A method is described for the preparation of a series of α-ketohiazole derivatives 1, 2, 3, and 4 which were assayed for proply endopeptidase inhibition. The potent inhibitors 1 and 2 possess a nitrogen atom at a position β to the adjoining ketone moiety.
A simple and convenient synthetic method for obtaining the novel bis(isoindolinones) 2a(-)d starting from aryl chlorides is described, using phenylimines with stoichiometric amounts of tetrakis(trimethylphosphine)nickel(0) as starting materials under a CO atmosphere (1 bar) at room temperature. The formation mechanism was proposed and discussed. The intermediate chelate arylnickel(II) complex 5d was also isolated and structurally characterized.
To detect possible molecular determinants of amnesia-reverting activity, the conformational properties of a number of rigid and flexible piracetam-type cognition enhancers have been assessed by X-ray diffraction, NMR spectroscopy, and ab initio and high-temperature-quenched molecular dynamics (QMD) calculations. The structures of the preferred conformers in solution derived from 1H-NMR spectral analysis were in good agreement with those found by QMD calculations. Interestingly, the calculation of the average molecular lipophilicity potential on the water-accessible surface of the selected conformers was helpful in interpreting the partitioning behavior observed by measuring octanol-water partition coefficients and capacity factors in reversed-phase high-performance liquid chromatography. While lipophilicity does not play a relevant role, the distance between polar groups, accounted for by the distance between carbonyl oxygens, emerges as a factor, among others, which should influence the amnesia-reversal activity of piracetam-type nootropics.
Some new N-substituted pyrrolidin-2-ones, cyclic analogues of baclofen and of 3-(5-methoxybenzo-[b]furan-2-yl)--aminobutyric acid, have been prepared and characterized, starting from 4-(4-chlorophenyl)-pyrrolidin-2-one and 4-(5-methoxybenzo[b]furan-2-yl)pyrrolidin-2-one.
The neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB) have emerged as key mediators in the pathophysiology of several mood disorders, including anxiety and depression. However, therapeutic compounds that interact with TrkB receptors have been difficult to develop. Using a combination of structure-based in silico screening and high-capacity functional assays in recombinant and neuronal cells, we identified a low-molecular weight TrkB ligand (ANA-12) that prevented activation of the receptor by BDNF with a high potency. ANA-12 showed direct and selective binding to TrkB and inhibited processes downstream of TrkB without altering TrkA and TrkC functions. KIRA-ELISA analysis demonstrated that systemic administration of ANA-12 to adult mice decreased TrkB activity in the brain without affecting neuronal survival. Mice administered ANA-12 demonstrated reduced anxiety- and depression-related behaviors on a variety of tests predictive of anxiolytic and antidepressant properties in humans. This study demonstrates that structure-based virtual screening strategy can be an efficient method for discovering potent TrkB-selective ligands that are active in vivo. We further propose that ANA-12 may be a valuable tool for studying BDNF/TrkB signaling and may constitute a lead compound for developing the next generation of therapeutic agents for the treatment of mood disorders.
A descriptive index (CI) based on the U statistic is presented. The CI permits to quantify the differences between experimental samples taking into account both the location and variability features of the data without any distributional assumption. This index can be useful to build activity scales for series of compounds.
Aminopeptidase P (APP), dipeptidyl peptidase II (DP II), dipeptidyl peptidase IV (DP IV) and prolyl oligopeptidase (POP) are proline specific peptidases. Hence, they are able to cleave peptide bonds containing the imino acid proline. Amino acid pyrrolidides (Pyrr) and thiazolidides (Thia) are well-known product analogue inhibitors of DP IV and POP. For the first time we describe the influence of a thioxo amide bond, incorporated into these compounds, on the inhibition of the proline specific peptidases. Taking into account the substrate specificity of these peptidases, we have synthesized Xaa-psi[CS-N]-Pyrr and Xaa-psi[CS-N]-Thia of the amino acids Ala, Phe, Val and Ile. The inhibition constants were determined for the above mentioned proline specific peptidases isolated from different sources. As a result, the serine proteases DP II, DP IV and POP were inhibited competitively, whereas metal-dependent APP displayed a linear mixed-type inhibition with inhibition constants up to 10(-4) M. Thioxylation of Xaa-Pyrr and Xaa-Thia led to a slight decrease of inhibition of DP IV and POP compared to Xaa-Pyrr and Xaa-Thia, though the inhibition constants were still in the range up to 10(-7) M. As Xaa-Thia exist as two isomers, we investigated isomer specific inhibition with regard to DP IV. Thus, our studies have revealed that DP IV was only inhibited by the Z isomer of the Xaa-psi[CS-N]-Thia. For the first time, Xaa-Pyrr and Xaa-Thia were characterized as inhibitors of DP II with inhibition constants in the micromolar range. In contrast to DP IV inhibition, the Xaa-psi[CS-N]-Pyrr and Xaa-psi[CS-N]-Thia have proven to be more potent inhibitors of DP II than the corresponding Xaa-Pyrr and Xaa-Thia. Thus, these Xaa-psi[CS-N]-Thia are new potent inhibitors especially suitable for DP II with K(i) values ranging in the upper nanomolar concentration.
The structural chemistry and biological activity of the bengamide class of compounds have been further characterized. Extracts prepared from recollected Jaspis cf. coriacea from five sites in Fiji were pooled. Six new bengamides, M (7b), N (8a), O (8b), P (9a), Q (9b), and R (10), were identified, accompanied by the known bengamides A (1a), B (1b), E (3a), F (3b), Y (5), Z (6), L (7a), G (11a), H (11b), and I (12). The structures of the new compounds were determined from spectroscopic data, and some were additionally confirmed by semisynthesis. Cytotoxicity screening data were obtained from the NCI-DTP 60 cell screen for bengamides A, B, and P. Bengamides A and B were more potent than bengamide P, with average IC(50) values of 0.046, 0.011, and 2.70 FM, respectively. The in vitro antitumor activity against MDA-MB-435 human mammary carcinoma was also determined for natural bengamides A, B, E, F, P, M, O, and Z and for synthetic samples of B and O. The best activity was observed for the natural bengamides A (IC(50) = 1 nM) and O (IC(50) = 0.3 nM).
The title compounds 1-(2-naphthyloxymethylcarbonyl)piperidine, C(17)H(19)NO(2), (I), and 3-methyl-1-(2-naphthyloxymethylcarbonyl)piperidine, C(18)H(21)NO(2), (II), are potential antiamnesics. In (II), the methyl-substituted piperidine ring is disordered over two conformations. The piperidine ring has a chair conformation in both compounds. In (I), the molecules are linked by weak intermolecular C-H.O interactions to give networks represented by C(4), C(6) and R(4)(4)(18) graph-set motifs, while in (II), weak intermolecular C-H.O interactions generate R(1)(2)(5), C(4) and C(7) graph-set motifs. The dihedral angle between the naphthalene moiety and the piperidine ring is 33.83 (7) degrees in (I), while it is 31.78 (11) and 19.38 (19) degrees for the major and minor conformations, respectively, in (II).
A new parametric quantum mechanical molecular model, AM1 (Austin Model 1), based on the NDDO approximation, is described. In it the major weaknesses of MNDO, in particular failure to reproduce hydrogen bonds, have been overcome without any increase in computing time. Results for 167 molecules are reported. Parameters are currently available for C, H, O, and N.
The bengamides A (Ia), E (Ib), C (II) and their N-methyl analogues, isobengamide E (III), the compounds (IV) and (V) and the known bengazoles (VI) are isolated from an undescribed Jaspidae sponge, which has been collected in the Benga lagoon of the Fiji Islands.
Memory mechanisms have many subclassifications that are mediated by a variety of neural processes. In a manner similar to the use of dopaminergics for the treatment of Parkinson's disease, one approach to the treatment of cognitive disorders targets a specific endogenous chemical system, whether a neurotransmitter, modulator, trophic factor, or hormone. Treatment with cholinesterase inhibitors is assumed to be limited by the availability of released acetylcholine. Animal studies with the cholinesterase inhibitor physostigmine, showed mixed results depending on the species, behavioral task, and length of treatment, but the clinical results have been generally disappointing. The influence of monoamines on learning and memory, and their dysfunction in dementias have been discussed in the chapter. In postmortem of Alzheimer's disease (AD) tissue, decreased concentrations of dopamine, norepinephrine (NE), serotonin (5-HT), and their metabolites have been reported. Treatment with clonidine, a α2-adrenergic agonist, improved memory in schizophrenics; but, its use with AD patients led to unacceptable hypotension. Researchers found that glutamate neurotoxicity has been implicated in cerebrovasciilar accidents, epilepsy, Huntington's disease, and AD. There may be a global somatostatin defect in AD that occurs beyond the genomic level, because somatostatin-linked deficits are found in cortex and hippocampus, hypothalamohypophyseal levels, and pancreatic endocrine function. The entire sequence may be necessary for memory enhancement. The prolyl endopeptidase (PEP) inhibitors, and perhaps some nootropics, may be affecting memory by prolonging the lifetime of endogenous neuropeptides critical to the cognitive process.
Current approaches do not provide the information needed for properly predicting drug effects in man.
The most stable conformations of four pyrrolidin-2-one derivatives, biologically active compounds, have been determined using the molecular mechanics method with different parametrizations and the quantum mechanical semiempirical AM1 method; the minima of the four potential energy hypersurfaces thus obtained were verified by SCF ab-initio calculations at the 3–21G level. Results indicate that the different methods single out minimum energy conformations characterized by similar geometries with the exception of the AM1 method which predicts a planar ring geometry instead of an envelope one. The geometries of the absolute minimum conformations are confirmed at the ab-initio level, while the relative minima, which generally have rather elevated relative energies (even larger then 4 kcal mol−1) and modest rotational interconversion barriers (< 0.5 kcal mol−1), are not confirmed.
Prolyl endopeptidase (PPCE) plays an important role in the degradation of biologically active peptides such as vasopressin which facilitates the process of learning and memory. Here, the effect of synthetic PPCE inhibitors (Z-Pro-, Suc-Pro-, Suc-Pyr-, Suc-Sar- and Z-prolinal) on the acquisition and retention of avoidance response was studied. Using mice of the ddY strain, tests were performed both in repeated trials of an active avoidance task and in a newly contrived one-trial passive-active avoidance task. The applicability of both tests for the evaluation of the anti-amnesic effect of the drugs was confirmed by the effect of scopolamine and arginine vasopressin (AVP). The most potent inhibitor, Z-Pro-prolinal, facilitated the acquisition of active avoidance response and retarded the extinction of the response. Other inhibitors also facilitated the retention of the acquired response. In the one-trial passive-active avoidance test, the facilitating effect of the PPCE inhibitors on the acquisition was parallel to their activity as a PPCE inhibitor. Scopolamine-induced amnesia was also improved by the inhibitors. These results suggest that the anti-amnesic effect of PPCE inhibitors is partially attributed to their inhibitory effect on the breakdown of AVP in the brain.
The term “nootropic” refers to compounds that act on cognitive functions. These drugs should facilitate learning and memory and prevent impairment of cognitive functions induced by diseases and brain insults. In animal models of impaired cognitive functions, the effects of several nootropic substances were investigated. Learning and retention in passive avoidance, and positive reinforcement paradigms were disrupted by hypoxia, cerebral ischemia and amnesia-inducing agents. Piracetam and several other novel nootropic compounds were shown to improve performance in these animal models. These results indicate that experimentally induced cognitive dysfunction in animals can be attenuated with drug treatment.
A complete set of intermolecular potential functions has been developed for use in computer simulations of proteins in their native environment. Parameters are reported for 25 peptide residues as well as the common neutral and charged terminal groups. The potential functions have the simple Coulomb plus Lennard-Jones form and are compatible with the widely used models for water, TIP4P, TIP3P, and SPC. The parameters were obtained and tested primarily in conjunction with Monte Carlo statistical mechanics simulations of 36 pure organic liquids and numerous aqueous solutions of organic ions representative of subunits in the side chains and backbones of proteins. Bond stretch, angle bend, and torsional terms have been adopted from the AMBER united-atom force field. As reported here, further testing has involved studies of conformational energy surfaces and optimizations of the crystal structures for four cyclic hexapeptides and a cyclic pentapeptide. The average root-mean-square deviation from the X-ray structures of the crystals is only 0.17 Å for the atomic positions and 3% for the unit cell volumes. A more critical test was then provided by performing energy minimizations for the complete crystal of the protein crambin, including 182 water molecules that were initially placed via a Monte Carlo simulation. The resultant root-mean-square deviation for the non-hydrogen atoms is still ca. 0.2 Å and the variation in the errors for charged, polar, and nonpolar residues is small. Improvement is apparent over the AMBER united-atom force field which has previously been demonstrated to be superior to many alternatives.
Upon leaving an elevated runway to enter a darkened chamber, male Wistar rats were given a single electric shock of .12, .25, or .50 ma. for 1, 3, or 9 sec. Retention trials, during which latency to enter the darkened chamber and defecation were recorded, were given immediately (30 sec.) or 3, 24, or 48 hr. after the shock trial. Latency and defecation were directly related to both the intensity and duration of the electric shock. No interaction between shock intensity and duration was observed. Reponse latency was inversely related to the retention interval. Although there was more defecation during the 3-hr test than during the immediate retention test, this could be interpreted as a recency effect rather than incubation of fear. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
This paper reports the complete amino acid chemistry of an undescribed Jaspidae sponge, collected annually in the Benga lagoon of the Fiji Islands during the period from 1984 to 1987. Five different amino acid types are represented among its constituents and they include the bengamides (six compounds), isobengamide E, bengazoles (A and B), a diketopiperazine cyclo(L-trans-(4-hydroxyprolinyl)-L-phenylalanine), and N-acetyl-L-phenylalanine methyl ester. The structures and stereochemical features of the bengamides were established by relying on analogies to bengamides A and B, along with insights gained by extensive spectroscopic and chemical degradation of isobengamide E and bengamide E. The chirality of the substituted ε-caprolactam ring of the bengamides was established as 10S and 13S by a combination of molecular mechanics calculations and hydrolysis of isobengamide E and bengamide E fragmentation products to obtain L-lysine hydrochloride. The relative stereochemistry of the 2(R*)-methoxy-3(R*),4(S*),5(R*)-trihydroxy-8-methylnon- 6(E)-enoyl side chain of the bengamides was based on analysis of 1H NMR J values of cyclized products. The bengazole structures have been previously established, and the structures of the remaining two amino acids were verified by synthesis. Biogenetic pathways are suggested for each of the most novel amino acid types.
The conformational features of ten known amnesia reversal compounds were analyzed by the molecular mechanics calculations with the aim of identifying a common spatial disposition of the polar functional groups present in all the molecules (a N-C=O amidic group and a X-C=O group, with X = O, N). Principal component analysis (PCA) led to the identification of three interatomic distances able to provide all the information necessary to describe the relative spatial disposition of the two functional groups. Cluster analysis was then performed to group the minimum energy conformations according to the values of those distances. Clusters were analyzed to single out those containing conformations of the maximum number of active compounds. This procedure permitted the finding of several acceptable pharmacophore models. The influence on results by the dissociated/undissociated forms of carboxylic compounds presented in the data set is also discussed. Two potent prolyl endopeptidase (PEP) inhibitors showing strong anti-amnesic effect were also included in the study. The results suggest that the common biological activity between these classes of compounds could be interpreted on the basis of the common spatial disposition of the investigated functional groups.
A general algorithm is described which exhaustively searches conformational space using an internal coordinate tree search. Using only geometrical operations and a set of criteria for eliminating chemically unreasonable structures, the algorithm generates starting geometries for optimization by molecular mechanics. An implementation of this algorithm is exceedingly fast and finds all known minima, as well as several new ones, for four test alkanes. This method makes feasible global conformational searches for molecules with up to 109 conformational possibilities.
We present an all atom potential energy function for the simulation of proteins and nucleic acids. This work is an extension of the CH united atom function recently presented by S.J. Weiner et al. J. Amer. Chem. Soc., 106, 765 (1984). The parameters of our function are based on calculations on ethane, propane, n−butane, dimethyl ether, methyl ethyl ether, tetrahydrofuran, imidazole, indole, deoxyadenosine, base paired dinucleoside phosphates, adenine, guanine, uracil, cytosine, thymine, insulin, and myoglobin. We have also used these parameters to carry out the first general vibrational analysis of all five nucleic acid bases with a molecular mechanics potential approach.
Pepeu, Giancarlo and Giacomo Spignoli: Nootroplc Drugs and Brain Cholinergic Mechanisms. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1989, (Suppl.): S77–S88 1.1. This review has two aims: first, to marshal and discuss evidences demonstrating an interaction between nootroplc drugs and brain cholinergic mechanisms; second, to define the relationship between the effects on cholinergic mechanisms and the cognitive process.2.2. Direct or indirect evidences indicating an activation of cholinergic mechanisms exist for pyrrolidinone derivatives including piracetam, oxiracetam, aniracetam, pyroglutamic acid, tenilsetam and pramiracetam and for miscellaneous chemical structures such as vinpocetine, naloxone, ebiratide and phosphatidylserine. All these drugs prevent or revert scopolamine-induced disruption of several learning and memory paradigms in animal and man.3.3. Some of the pyrrolidinone derivatives also prevent amnesia assiciated with inhibition of acetylcholine synthesis brought about by hemicholinium. Oxiracetam prevents the decrease in brain acetylcholine and amnesia caused by electroconvulsive shock. Oxiracetam, aniracetam and pyroglutamic acid prevent brain acetylcholine decrease and amnesia induced by scopolamine. Comparable bell-shaped dose-effect relationships result for both actions. Phosphatidylserine restores acetylcholine synthesis and conditioned responses in aging rats.4.4. The mechanisms through which the action on cholinergic systems might take place, including stimulation of the high affinity choline uptake, are discussed. The information available are not yet sufficient to define at which steps of the cognitive process the action on cholinergic system plays a role and which are the influences of the changes in cholinergic function on other neurochemical mechanisms of learning and memory.
1.1. Nootropic drugs were proposed as a class of psychoactive drugs that selectively improve efficiency of higher telencephalic integrative activities.2.2. The main features of the nootropic profile consist of: (a) enhancement of learning acquisition; (b) resistance to impairing agents; (c) facilitation of interhemispheric transfer of information; (d) enhanced resistance to brain “aggressions”; (e) increased tonic, cortico-subcortical “control”; and (f) absence of usual pharmacological effects of neuro psychotropic drugs.3.3. The animal experimental results are thoroughly corroborated by the data obtained in clinical pharmacology and pharmacotherapeutics supporting the concept that nootropic activity is based on a functional telencephalic selectivity.4.4. The basic mechanism of action at molecular and cellular levels of nootropic drugs is not yet known. Some recent data emphasized a possible role for cerebral ATP.
A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
Four derivatives of a known prolyl endopeptidase (PEP) inhibitor (N-[N-(phenyl)butyryl-L-propyl]pyrrolidine; SUAM-1221) were synthesized along with the parent compound. All five compounds were relatively potent, competitive inhibitors of rat brain and mouse brain and kidney PEP, with IC50S in the range of 3-27 nM. Ex vivo experiments showed that all compounds penetrated into the CNS and produced inhibition of brain PEP, although inhibition was not as great as in the periphery (kidney PEP). Each compound had a similar time course of duration, with maximum inhibition of brain PEP being achieved within 5-10 min after i.p. administration, with inhibition of brain PEP (up to 20%) still present 6 h after dosing. However, two of the compounds, SUAM-1221 and its amine derivative, had ED50S versus mouse brain PEP (1-3 mg/kg) an order of magnitude less than the other compounds (25-40 mg/kg). Administration of the amine compound resulted in a significant partial reversal of the deficit in memory performance produced by scopolamine.
In the first article in this series, Watkins, Krogsgaard-Larsen and Honoré outlined the structure-activity requirements at the receptor sites for excitatory amino acids in the mammalian CNS. The postsynaptic depolarizing actions of glutamate are thought to be mediated by NMDA, AMPA and kainate receptors. Here David Lodge and Kenneth M. Johnson review some of the recent developments in the pharmacology of other means by which the function of these receptors may be modulated. Divalent cations, phencyclidine-like drugs, glycine analogues and polyamines all modulate NMDA receptors whereas barbiturates and some arthropod toxins reduce channel responses to non-NMDA receptor agonists. Modes of action and implications for physiology and pathophysiology are discussed.
Merlini, Lucio and Mario Pinza: Trends in Searching for New Cognition Enhancing Drugs. Prog. Neuro-Psychopharmacol. & Biol. Psychiat. 1989,13 (Suppl.): s61-S75 1. 1. The great interest for new drugs having cognition enhancing properties is highlighted, particularly for the treatment of dementia of Alzheimer type. 2. 2. A short survey is given of the pharmacological models currently used to mimic cognitive impairment. 3. 3. A systematic survey is given of the major cognition enhancing drugs and of the new compounds showing activity.
Using rats in one-trial passive avoidance tests, the anti-amnesic effects of the nootropic drug aniracetam were investigated; moreover, the action of aniracetam upon the cholinergic system in the brain was studied. In one-trial passive avoidance tests, aniracetam prolonged significantly the retention time for 100 mg/kg, p.o. However, the retention-prolonging effect was diminished when the dose was increased to 300 mg/kg p.o. Investigation of the action of the drug upon the cholinergic system revealed that ACh and choline content in the corpus striatum was not increased by any doses of aniracetam. ACh content in the hippocampus was increased by doses of 100-300 mg/kg, p.o., but choline was not significantly increased by any doses, while in the cerebral cortex ACh content was significantly increased by a dose of 300 mg/kg, p.o. In addition, the decrease in hippocampal ACh and choline content following an injection of scopolamine was lessened by aniracetam 100 mg/kg, p.o. and 100-300 mg/kg, respectively. In order to elucidate the mechanism of these actions of aniracetam, the ACh-releasing action and changes in choline content of the extracellular spaces in the hippocampus were investigated, but no effects were observed. The results obtained indicate that aniracetam has an inhibitory effect upon scopolamine-induced amnesia. The mechanism of this effect may be an action upon the cholinergic system; therefore, some action with respect to the impairment of cholinergic neurotransmission in the hippocampus induced by scopolamine appears to be of particular importance.
Scopolamine (3 mg/kg IP) given before an acquisition trial, reduced the retention of a one-trial passive avoidance "step through" response in mice. A single administration of cholinergic agonists such as oxotremorine, BM-5, or arecoline, antagonized this amnesic effect of scopolamine. A significant anti-amnesic effect was also found with nootropic drugs such as piracetam and ucb L059, whereas ucb L060 (the enantiomer of ucb L059), oxiracetam and rolziracetam were shown to be ineffective. Moreover, ucb L059, administered twice daily for 3 days, counteracted the amnesic effects of scopolamine completely, whereas ucb L060 was again inactive. The results demonstrate that: (a) this model of impaired cognition by scopolamine is able to discriminate between closely related chemical substances and even stereoisomers; and (b) nootropic drugs, such as ucb L059, are more effective after repeated rather than after acute administration.
Several peptides and peptide derivatives were tested for their inhibitory effect on prolyl endopeptidase and possible properties as anti-amnesic agents. Among the compounds tested, Z-Gly-Pro-CH2Cl, Z-Val-prolinal, Boc-Pro-prolinal, Z-Pro-prolinal, aniracetam and pramiracetam inhibited the enzyme activities at Ki values in the order of nM to microM, and the effect of the prolinal-containing peptide derivatives was specific for prolyl endopeptidase. Z-Pro-prolinal was the most effective inhibitor in vitro (Ki = 5 nM) and in vivo (50 to 70% inhibition in various organs of rat at a dose of 1 mumol/animal i.p.). Regional differences were observed in the effect of inhibitors on the brain enzyme activities: most active in mesencephalon, followed by striatum, cerebellum, hippocampus, hypothalamus; and inactive in cerebral cortex and medulla oblongata. In the passive avoidance learning test using rats, pretreatment with Z-Pro-prolinal prevented the induction of amnesia by scopolamine at the dose of 1 mumol/animal, i.p. Z-Val-prolinal, Z-Pyr-prolinal and Z-Gly-Pro-CH2Cl were also effective in the retention test at 24 and 48 h after the training trial. The antiamnesic effect of these compounds was approximately parallel to the in vitro inhibitory activities on prolyl endopeptidase. These results suggest the possibility that the inhibitors exhibit their anti-amnesic effect through the regulation of the enzyme activity in the brain.
The effect of cognition-enhancing agents oxiracetam and aniracetam on scopolamine-induced amnesia and brain acetylcholine decrease was investigated in the rat. Acetylcholine levels were measured by means of a gas-chromatographic method. Scopolamine (0.63 mg/kg IP 60 min before training) prevented the acquisition of a passive avoidance conditioned response ("step through": retest 30 min after training) and brought about a 64, 56 and 42% decrease in acetylcholine level in the cortex, hippocampus and striatum respectively. Oxiracetam (50 and 100 mg/kg IP) administered 30 min before scopolamine reduced the scopolamine-induced amnesic effect and decrease in acetylcholine level in the cortex and hippocampus, but not in the striatum. Lower and higher doses of oxiracetam were ineffective. Aniracetam (100 mg/kg PO) also prevented scopolamine-induced amnesia but attenuated acetylcholine decrease in the hippocampus only. Aniracetam (300 mg PO) reduced acetylcholine decrease in the hippocampus but did not prevent scopolamine-amnesia. In conclusion, oxiracetam and aniracetam exert a stimulatory effect on specific central cholinergic pathways. However, a direct relationship between cognition-enhancing properties and cholinergic activation needs further confirmation.
The use of graded data from hot-plate antinociceptive tests is complicated by the problem of how to treat responses that are greater than the cut-off time. This paper describes a statistical procedure for analysis of antinociceptive data that circumvents this problem. The method is based upon the likelihood function and the data is assumed to follow a Weibull distribution. The technique can be implemented with the use of a computer and provides a more comprehensive assessment of antinociceptive data.
A series of N-[(dialkylamino)alkyl]-2-oxo-1- pyrrolidineacetamides was synthesized. The title compounds reversed electroconvulsive shock (ECS) induced amnesia in mice when administered subsequent to the ECS treatment and were inactive in a general observational test for central nervous system (CNS) activity. Active compounds exhibited an inverted U-shaped dose-response curve. Among the compounds with the broadest dose-response curve, as well as the most potent, were those with the N-[2-[bis(1-methylethyl)amino] ethyl] or 2,6- dimethylpiperidinoethyl residues as amide substituent. The N-(dialkylamino) substituent markedly enhances amnesia-reversal activity, with ethylene providing the optimal chain length. N-[2-[Bis(1-methylethyl)amino]ethyl] -2-oxo-1- pyrrolidineacetamide N-(dialkylamino) substituent was selected for preclinical toxicological evaluation, assigned the investigational number CI-879 and the U.S. adopted name ( USAN ) pramiracetam . Pramiracetam demonstrated a wide margin of safety in animals and was well tolerated in normal human volunteers. It has shown encouraging activity in an open label trial in patients with primary degenerative dementia (PDD or senile dementia of the Alzheimer's type).
The effect of aniracetam (Ro 13-5057, 1-anisoyl-2-pyrrolidinone) was studied on various forms of experimentally impaired cognitive functions (learning and memory) in rodents and produced the following effects: (1) almost complete prevention of the incapacity to learn a discrete escape response in rats exposed to sublethal hypercapnia immediately before the acquisition session; (2) partial (rats) or complete (mice) prevention of the scopolamine-induced short-term amnesia for a passive avoidance task; (3) complete protection against amnesia for a passive avoidance task in rats submitted to electroconvulsive shock immediately after avoidance acquisition; (4) prevention of the long-term retention- or retrieval-deficit for a passive avoidance task induced in rats and mice by chloramphenicol or cycloheximide administered immediately after acquisition; (5) reversal, when administered as late as 1 h before the retention test, of the deficit in retention or retrieval of a passive avoidance task induced by cycloheximide injected 2 days previously; (6) prevention of the deficit in the retrieval of an active avoidance task induced in mice by subconvulsant electroshock or hypercapnia applied immediately before retrieval testing (24 h after acquisition). These improvements or normalizations of impaired cognitive functions were seen at oral aniracetam doses of 10-100 mg/kg. Generally, the dose-response curves were bell-shaped. The mechanisms underlying the activity of aniracetam and its 'therapeutic window' are unknown. Piracetam, another pyrrolidinone derivative was used for comparison. It was active only in six of nine tests and had about one-tenth the potency of aniracetam. The results indicate that aniracetam improves cognitive functions which are impaired by different procedure and in different phases of the learning and memory process.
Stereochemistry and Synthesis of Several New Heterocycles
- Structures
Structures, Stereochemistry and Synthesis of Several New Heterocycles. J. Am. Chem. SOC. 1989,111,647-654.
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