6-(1S)-1-1-5-(2-hydroxyethoxy)-2-pyridylpyrazol-3-ylethyl-3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor ...regulatory protein (TARP) γ−8. This molecule has been characterized as a potent and efficacious anticonvulsant in an array of acute and chronic epilepsy models in rodents. The present set of experiments was designed to assess the effects of LY3130481 on the electroencephelogram (EEG), cognitive function, and neurochemical outflow. LY3130481 disrupted food-maintained responding in rats and spontaneous alternation in a Y-maze in mice. In rat fear conditioning, LY3130481 caused a deficit in trace (hippocampal-dependent), but not in delay fear conditioning. Although these effects on cognitive performances were observed, the known cognitive-impairing anticonvulsant, topiramate, did not always produce deficits under these assay conditions. LY3130481 produced modest increases in wake times in rats. In addition, LY3130481 was able to attenuate some impairing effects of standard antiepileptic drugs. The motor-impairing effects of the lacosamide were attenuated by LY3130481 as was the decrease in non-rapid-eye movement sleep induced by carbamazepine. Evaluation of the effect of LY3130481 on neurotransmitter and metabolite efflux in the rat medial prefrontal cortex, using in vivo microdialysis, revealed significant increases in the pro-cognitive and wake-promoting neurotransmitters, histamine and acetylcholine, as well as in serotonin, telemethylhistamine, 5-HIAA, HVA and MHPG. LY3130481 thus presents a novel behavioral profile that will have to be evaluated in patients to fully appreciate its implications for therapeutics. LY3130481 is currently under clinical development as CERC-611 as an antiepileptic.
•LY3130481 (CERC-611) is a selective antagonist of AMPA receptors TARP γ−8 protein.•LY3130481 is currently under clinical development as CERC-611 as an antiepileptic.•LY3130481 produced mixed results in rodent cognition assessments.•LY3130481 produced modest increases in wake times in rats and increased wake and cognition-associated neurotransmitters.•LY3130481 attenuated some impairing effects of standard antiepileptic drugs.
The normalization of excessive glutamatergic neurotransmission through the activation of metabotropic glutamate 2 (mGlu2) receptors may have therapeutic potential in a variety of psychiatric ...disorders, including anxiety/depression and schizophrenia. Here, we characterize the pharmacological properties of N-(4-((2-(trifluoromethyl)-3-hydroxy-4-(isobutyryl)phenoxy)methyl)benzyl)-1-methyl-1H-imidazole-4-carboxamide (THIIC), a structurally novel, potent, and selective allosteric potentiator of human and rat mGlu2 receptors (EC(50) = 23 and 13 nM, respectively). THIIC produced anxiolytic-like efficacy in the rat stress-induced hyperthermia assay and the mouse stress-induced elevation of cerebellar cGMP and marble-burying assays. THIIC also produced robust activity in three assays that detect antidepressant-like activity, including the mouse forced-swim test, the rat differential reinforcement of low rate 72-s assay, and the rat dominant-submissive test, with a maximal response similar to that of imipramine. Effects of THIIC in the forced-swim test and marble burying were deleted in mGlu2 receptor null mice. Analysis of sleep electroencephalogram (EEG) showed that THIIC had a sleep-promoting profile with increased non-rapid eye movement (REM) and decreased REM sleep. THIIC also decreased the dark phase increase in extracellular histamine in the medial prefrontal cortex and decreased levels of the histamine metabolite tele-methylhistamine (t-MeHA) in rat cerebrospinal fluid. Collectively, these results indicate that the novel mGlu2-positive allosteric modulator THIIC has robust activity in models used to predict anxiolytic/antidepressant efficacy, substantiating, at least with this molecule, differentiation in the biological impact of mGlu2 potentiation versus mGlu2/3 orthosteric agonism. In addition, we provide evidence that sleep EEG and CSF t-MeHA might function as viable biomarker approaches to facilitate the translational development of THIIC and other mGlu2 potentiators.
Modafinil, a novel compound for treating excessive sleepiness, potently increases wakefulness in laboratory rodents, cats, monkeys and humans. Although its mechanism of action is unknown, modafinil ...appears to be unlike classic stimulants. We investigated this generality by testing the selectivity of this compound for wake-promoting effects (e.g., relative to locomotor effects) and homeostatic sleep responses after drug-induced waking relative to the prototypical stimulant methamphetamine (METH). Continuous measures of electroencephalogram (EEG) sleep-wakefulness, locomotor activity (LMA) and body temperature (Tb) were obtained from adult male Wistar rats 3 days before and after treatment with modafinil (30, 100 and 300 mg/kg i.p.), 0.25% methylcellulose (vehicle) or METH (0.5 and 1.0 mg/kg i.p.). Individually housed rats in a 24-h light-dark cycle (LD 12:12) were treated 5 h after lights-on (CT-5). LMA and Tb were monitored via intraperitoneal telemetry. Sleep-wake stages and LMA were recorded every 10 s, Tb every minute. During the first 3 h post-treatment, modafinil and METH significantly and dose-dependently increased EEG wake time (P < .01 for 30 mg/kg modafinil, all other P < .0001) and wake episode duration. Although the cumulative increases in wakefulness were statistically equivalent, METH, but not modafinil, produced subsequent rebound hypersomnolence. At these equipotent wake-promoting doses, modafinil produced the same total amount of REM sleep inhibition but during a longer time than METH. Modafinil also increased LMA amount (counts/h, P < .001) and LMA intensity (counts/min awake, P < .001) less than METH. Both rebound hypersomnolence and increased LMA intensity, which are undesirable features in wake-promoting drugs, were not observed after modafinil treatment, and thus further differentiated modafinil from amphetamine-like stimulants.
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Negative modulators of metabotropic glutamate 2 & 3 receptors demonstrate antidepressant-like activity in animal models and hold promise as novel therapeutic agents for the treatment ...of major depressive disorder. Herein we describe our efforts to prepare and optimize a series of conformationally constrained 3,4-disubstituted bicyclo3.1.0hexane glutamic acid analogs as orthosteric (glutamate site) mGlu2/3 receptor antagonists. This work led to the discovery of a highly potent and efficacious tool compound 18 (hmGlu2 IC50 46±14.2nM, hmGlu3 IC50=46.1±36.2nM). Compound 18 showed activity in the mouse forced swim test with a minimal effective dose (MED) of 1mg/kg ip. While in rat EEG studies it exhibited wake promoting effects at 3 and 10mg/kg ip without any significant effects on locomotor activity. Compound 18 thus represents a novel tool molecule for studying the impact of blocking mGlu2/3 receptors both in vitro and in vivo.
An endogenous neuroactive steroid, pregnanolone, and an orally available synthetic analog, CCD-3693, were administered to rats at the middle of their circadian activity phase (6 hr after lights off). ...Electroencephalogram-defined sleep-wake states, locomotor activity and body temperature were concurrently measured 30 hr before and after treatment. Identical procedures were used to test triazolam and zolpidem. Triazolam (0.1-1.6 mg/kg), zolpidem (2.5-10 mg/kg) and the neuroactive steroids (10-30 mg/kg) produced dose-dependent increases in non-rapid eye movement (NREM) sleep. At this dose and time of day (in which the rats were predominantly awake during the 6 hr before treatment) the neuroactive steroids appeared more intrinsically efficacious in promoting NREM sleep than the benzodiazepine ligands. The neurosteroids did not, however, significantly interfere with rapid eye movement sleep and were more selective in reducing (EEG) wakefulness, with relatively less locomotor activity impairment during waking than triazolam and zolpidem. In addition, the benzodiazepine receptor ligands showed distinct "rebound" wakefulness after the NREM sleep-promoting effect subsided, although the neuroactive steroids did not. In addition, in vitro binding studies and in vivo pharmacological data confirmed that CCD-3693 was orally active in standard tests of anxiety, anticonvulsant, loss-of-righting and passive avoidance.
The electroencephalogram (EEG) and electromyogram of rats with lesions in the suprachiasmatic nuclei (SCNx) were recorded during two series of 24-h baseline, 6-h sleep deprivation (SD), and 24-h ...recovery. At recovery onset, rats were injected i.p. with vehicle (VEH) control solution or 0.4 mg/kg triazolam (TRZ) in a balanced crossover design. Consecutive 10-s epochs were scored for vigilance states and EEG power spectra were computed. Arousal states were uniformly distributed during 24-h baseline (wake 47% of recording time, non-rapid-eye movement sleep (nonREMS) 47%, REMS 7%), and EEG spectra (0-25 Hz) were devoid of significant trends. State-specific EEG power spectra profiles in SCNx rats were similar to those of intact animals reported previously. However, EEG delta power (0.5-3.5 Hz) of nonREMS was markedly lower in SCNx rats. Recovery from 6-h SD was characterised by a short-lasting reduction of REMS, and a long-lasting increase of nonREMS time at the cost of wakefulness. EEG delta power rebounded during the first 8 h in recovery, and fell below baseline level after 12 h in recovery. During 0-2 h TRZ recovery, rats spent more time in nonREMS with higher EEG slow wave activity as compared to the corresponding VEH recovery period. EEG slow wave activity fell below baseline levels 10 h after TRZ injection and termination of SD. We conclude that major features of homeostatic sleep EEG regulation are present in SCNx rats.
O Reconhecimento de Entidades Mencionadas (REM) é uma subtarefa da extração de informações e tem como objetivo localizar e classificar elementos do texto em categorias pré-definidas tais como nome de ...pessoas, organizações, lugares, datas e outras classes de interesse. Esse conhecimento obtido possibilita a execução de outras tarefas mais avançadas. O REM pode ser considerado um dos primeiros passos para a análise semântica de textos, além de ser uma subtarefa crucial para sistemas de gerenciamento de documentos, mineração de textos, extração da informação, entre outros. Neste trabalho, estudamos alguns métodos de Aprendizado de Máquina aplicados na tarefa de REM que estão relacionados ao atual estado da arte, dentre eles, dois métodos aplicados na tarefa de REM para a língua portuguesa. Apresentamos três diferentes formas de avaliação destes tipos de sistemas presentes na literatura da área. Além disso, desenvolvemos um sistema de REM para língua portuguesa utilizando Aprendizado de Máquina, mais especificamente, o arcabouço de máxima entropia. Os resultados obtidos com o nosso sistema alcançaram resultados equiparáveis aos melhores sistemas de REM para a língua portuguesa desenvolvidos utilizando outras abordagens de aprendizado de máquina.
Named Entity Recognition (NER), a task related to information extraction, aims to classify textual elements according to predefined categories such as names, places, dates etc. This enables the execution of more advanced tasks. NER is a first step towards semantic textual analysis and is also a crucial task for systems of information extraction and other types of systems. In this thesis, I analyze some Machine Learning methods applied to NER tasks, including two methods applied to Portuguese language. I present three ways of evaluating these types of systems found in the literature. I also develop an NER system for the Portuguese language utilizing Machine Learning that entails working with a maximum entropy framework. The results are comparable to the best NER systems for the Portuguese language developed with other Machine Learning alternatives.
The effect of the dopamine autoreceptor antagonist (-)DS121 on wakefulness, locomotor activity, body temperature and subsequent compensatory sleep responses was examined in the rat. Animals entrained ...to a light-dark cycle were treated at 5 h after lights-on (CT-5) with 0.5, 1, 5 or 10 mg/kg i.p. (-)DS121 or methylcellulose vehicle. An additional group received 5 mg/kg i.p. (-)DS121 or vehicle 6 h after lights-off (CT-18). At CT-5, (-)DS121 dose-dependently increased wakefulness, locomotor activity and body temperature, and decreased both non-rapid eye movement sleep (NREM) and rapid eye movement sleep (REM) during the first 4 h post-treatment relative to vehicle controls. REM interference lasted up to 3 h longer than NREM. Low doses of (-)DS121 (0.5 and 1 mg/kg) produced relatively little waking that was not followed by significant compensatory sleep responses. In contrast, higher doses (5 and 10 mg/kg) produced compensatory hypersomnolence (robust increases in NREM immediately after the primary waking effect) that was proportional to the duration of drug-induced wakefulness. NREM recovery 24 h post-treatment was the same for the 5 mg/kg (65.4 +/- 9.9 min) and 10 mg/kg (64.8 +/- 9.3 min) doses, but was not proportional to prior wake duration. NREM displaced by drug-induced wakefulness was recovered completely by 24 h post-treatment at the 5 mg/kg dose, but only 63.5% recovered at 10 mg/kg. In contrast, equivalent wakefulness produced by sleep deprivation yielded 100% NREM recovery. At CT-18, (-)DS121 (5 mg/kg) increased wakefulness without disproportionately increasing locomotor activity, and was compensated fully by 24 h post-treatment. These data show that (-)DS121 dose-dependently increases wakefulness, which is followed by hypersomnolence that is proportional to drug-induced wake-promoting efficacy.
Novel neuroactive steroids were evaluated for their effects on operant responding, rotorod motor performance, and electroencephalogram recording in rats. Co 134444, Co 177843, and Co 127501 were ...compared with the prototypical gamma-aminobutyric acid(A)-positive allosteric modulators triazolam, zolpidem, pentobarbital, pregnanolone, and CCD 3693. Each of the compounds produced a dose-related decrease in response rates under a variable-interval 2-min schedule of positive reinforcement in an operant paradigm. In addition, all compounds produced a dose-related increase in ataxia and significant increases in nonrapid eye movement sleep in this experiment or have been previously reported to do so. Co 134444, Co 177843, and Co 127501 increased nonrapid eye movement sleep at doses that had no effect on rapid eye movement sleep. All of the compounds were more potent at decreasing operant responding than they were at increasing ataxia. Furthermore, the potency of compounds to produce response-rate suppression in an operant paradigm appeared to be a better predictor of soporific potency than did potency in the rotorod assay. The screening for sedative-hypnotic activity resulted in the identification of the novel orally active neuroactive steroids Co 134444, Co 177843, and Co 127501.
Normal sleepers underwent sleep recordings and daytime tests of sleep tendency, performance, and moode while being shifted 180° in their sleep-wake schedule. After two baseline 24-hour periods, ...subjects postponed sleep until noon. For the next three 24-hour periods, they were in bed from 1200 to 2000 and received triazolam, flurazepam, or placebo at bedtime in parallel groups. Placebo subjects showed significant sleep loss after the shift. Active medication reversed this sleep loss. Despite good sleep, flurazepam subjects appeared most impaired of the three groups on objective assessments of waking function; triazolam subjects were least impaired.
![Novel bicyclo[3.1.0]hexane ...](http://api.summon.serialssolutions.com/2.0.0/image/issn/XR4PS5YY4K/0960-894X/small "Novel bicyclo[3.1.0]hexane analogs as antagonists of metabotropic glutamate 2/3 receptors for the treatment of depression")
