RESUMEN
BACKGROUND: N-methyl-D-aspartate (NMDA) receptor activation requires the binding of a co-agonist on the glycine-binding site. D-serine is the main endogenous co-agonist of NMDA receptors, and its availability significantly depends on the activity of the metabolic enzyme D-amino acid oxidase (DAAO). Inhibition of DAAO increases the brain levels of D-serine and modulates a variety of physiological functions, including cognitive behavior. METHODS: Here, we examined the effects of a novel 4-hydroxypyridazin-3(2H)-one derivative DAAO inhibitor, Compound 30 (CPD30), on passive avoidance learning and on neuronal firing activity in rats. RESULTS: D-serine administration was applied as reference, which increased cognitive performance and enhanced hippocampal firing activity and responsiveness to NMDA after both local and systemic application. Similarly to D-serine, CPD30 (0.1 mg/kg) effectively reversed MK-801-induced memory impairment in the passive avoidance test. Furthermore, local iontophoretic application of CPD30 in the vicinity of hippocampal pyramidal neurons significantly increased firing rate and enhanced their responses to locally applied NMDA. CPD30 also enhanced hippocampal firing activity after systemic administration. In 0.1- to 1.0-mg/kg doses, CPD30 increased spontaneous and NMDA-evoked firing activity of the neurons. Effects of CPD30 on NMDA responsiveness emerged faster (at 10 minutes post-injection) when a 1.0-mg/kg dose was applied compared with the onset of the effects of 0.1 mg/kg CPD30 (at 30 minutes post-injection). CONCLUSIONS: The present results confirm that the inhibition of DAAO enzyme is an effective strategy for cognitive enhancement. Our findings further facilitate the understanding of the cellular mechanisms underlying the behavioral effects of DAAO inhibition in the mammalian brain.
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Reacción de Prevención/efectos de los fármacos , Conducta Animal/efectos de los fármacos , D-Aminoácido Oxidasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Hipocampo/efectos de los fármacos , Trastornos de la Memoria/tratamiento farmacológico , Nootrópicos/farmacología , Células Piramidales/efectos de los fármacos , Compuestos de Piridinio/farmacología , Potenciales de Acción/efectos de los fármacos , Animales , Inhibidores Enzimáticos/administración & dosificación , Agonistas de Aminoácidos Excitadores/farmacología , Hipocampo/enzimología , Masculino , Trastornos de la Memoria/enzimología , N-Metilaspartato/farmacología , Nootrópicos/administración & dosificación , Compuestos de Piridinio/administración & dosificación , Ratas , Ratas WistarRESUMEN
N-methyl-d-aspartate receptors (NMDARs) play an important role in excitatory neurotransmission and have been associated with psychiatric conditions including schizophrenia and major depressive disorder. NMDARs are composed of two NR1 and two NR2 subunits. The type of NR2 subunit determines electrophysiological and pharmacological properties of the receptor. As the precise role of NR2C/D subunit-containing NMDARs is poorly understood in vivo, we have performed behavioural, quantitative electroencephalographic (qEEG) and polysomnographic analysis following acute pharmacological blockade of these receptor subtypes in adult male CD1 mice. We found that NR2C/D blockade impaired motor coordination and decreased the amount of gross movement. Moreover, EEG power in multiple frequency bands including theta and sigma were found to decrease significantly together with a decrease of theta oscillation frequency. Changes of these qEEG measures were accompanied by a decrease in time spent in slow-wave and rapid eye movement sleep, but an increase of time spent in quiet wakefulness. Furthermore, there was a significant decrease of sleep spindle oscillation density. These findings highlight the importance of NR2C/D-containing NMDARs and take a step towards establishing a link between electrophysiological correlates of psychiatric disorders and underlying synaptic dysfunctions.
Asunto(s)
Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Sueño , Animales , Trastorno Depresivo Mayor/metabolismo , Electroencefalografía , Masculino , Ratones , Esquizofrenia/metabolismo , VigiliaRESUMEN
To further proceed with our previous work, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Using an 'amine-to-amide' modification strategy at position 17, in vitro and in vivo potent monoamino steroid derivatives were found during the lead optimization. Usage of the non-basic amide moiety resulted in beneficial effects both in activity and selectivity. The 15α-carboxamido derivative 10 was not only highly active at human and rat H3 receptors, but also showed negligible activity at rat muscarinic receptors. Furthermore, it proved to be considerably stable in human and rat microsomes and showed significant in vivo potency in the pharmacodynamic rat dipsogenia test and in the water-labyrinth cognitive model. Based on all of these considerations, compound 10 was appointed to be a preclinical candidate.
Asunto(s)
Amidas/química , Antagonistas de los Receptores Histamínicos/química , Receptores Histamínicos H3/metabolismo , Amidas/farmacología , Animales , Antagonistas de los Receptores Histamínicos/metabolismo , Humanos , Masculino , Estructura Molecular , Contracción Muscular/efectos de los fármacos , Ratas , Ratas Wistar , Receptores Muscarínicos/química , Solubilidad , Esteroides/químicaRESUMEN
Automated homecage monitoring systems are now widely recognized and used tools in cognitive neuroscience. However, few of these studies cover pharmacological interventions. Scopolamine, an anticholinergic memory disrupting agent is frequently used to study learning behavior. We studied the impact of scopolamine treatment in a relevant dose-range on activity, drinking behavior and reversal learning of C57BL/DJ mice in a homecage-like, social environment, using the IntelliCage. Naïve mice were first habituated to the IntelliCage, where they learned to nosepoke in any of the four corners in order to gain access to the water reward. Visits, nosepokes, lick numbers and durations were recorded. Mice were then trained to distinguish between a rewarded correct corner and punished, incorrect corners. Later, in the reversal learning phase, the assigned correct corner was rotated clockwise every 24 h. Upon s.c. administration of scopolamine general activity represented by visit and nosepoke numbers increased, but their durations were shorter. Surprisingly, general activity and lick behavior were drastically altered. Scopolamine also significantly reduced the ability to perform a reversal learning task. We not only found significant decline in reversal learning due to scopolamine treatment, but studied the method specific underlying behaviors: the general activity and lick behavior as well.
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Conducta Animal/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Aprendizaje Inverso/efectos de los fármacos , Escopolamina/farmacología , Animales , Masculino , Memoria/efectos de los fármacos , Ratones Endogámicos C57BL , RecompensaRESUMEN
Emerging from an HTS campaign, novel steroid-based histamine H3 receptor antagonists were identified and characterized. Structural moieties of the hit compounds were combined to improve binding affinities which resulted in compound 4 as lead molecule. During the lead optimization due to the versatile modifications of diamino steroid derivatives, several in vitro potent compounds with subnanomolar binding affinities to histamine H3 receptors were found. The unfavorable binding to rat muscarinic receptors was successfully reduced by tuning the basicity. Compound 20 showed significant in vivo activity in the rat dipsogenia model and could serve as a pharmacological tool in the future.
Asunto(s)
Descubrimiento de Drogas , Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores Histamínicos H3/farmacología , Receptores Histamínicos H3/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Agonistas de los Receptores Histamínicos/síntesis química , Agonistas de los Receptores Histamínicos/química , Antagonistas de los Receptores Histamínicos H3/síntesis química , Antagonistas de los Receptores Histamínicos H3/química , Humanos , Estructura Molecular , Ratas , Relación Estructura-ActividadRESUMEN
The Fawn-hooded rat has long been used as a model for various peripheral and central disorders and the data available indicate that the social behavior of this strain may be compromised. However, a thorough description of the Fawn-hooded rat is unavailable in this regard. The objective of the present study was to investigate various aspects of the Fawn-hooded rat's social behavior in depth. Our results show that several facets of socio-communicational behavior are impaired in the RjIbm(m):FH strain, including defective ultrasonic vocalizations in pups upon maternal deprivation, reduced social play in adolescence and impaired social novelty discrimination in adulthood. In addition, Fawn-hooded rats exhibited heightened tactile sensitivity and hyperactivity. The defects observed were comparable to those induced by prenatal valproate exposure, a widely utilized model of autism spectrum disorder. Further on, the pro-social drug R-baclofen (0.25-1 mg/kg) reversed the autistic-like defects observed in Fawn-hooded rats, specifically the deficiency in ultrasonic vocalization, tactile sensitivity and social novelty discrimination endpoints. In conclusion, the asocial, hypersensitive and hyperactive phenotype as well as the responsivity to R-baclofen indicate this variant of the Fawn-hooded rat strain may serve as a model of autism spectrum disorder and could be useful in the identification of novel drug candidates.
RESUMEN
Steroid-based histamine H3 receptor antagonists (d-homoazasteroids) were designed by combining distinct structural elements of HTS hit molecules. They were characterized, and several of them displayed remarkably high affinity for H3 receptors with antagonist/inverse agonist features. Especially, the 17a-aza-d-homolactam chemotype demonstrated excellent H3R activity together with significant in vivo H3 antagonism. Optimization of the chemotype was initiated with special emphasis on the elimination of the hERG and muscarinic affinity. Additionally, ligand-based SAR considerations and molecular docking studies were performed to predict binding modes of the molecules. The most promising compounds (XXI, XXVIII, and XX) showed practically no muscarinic and hERG affinity. They showed antagonist/inverse agonist property in the in vitro functional tests that was apparent in the rat in vivo dipsogenia test. They were considerably stable in human and rat liver microsomes and provided significant in vivo potency in the place recognition and novel object recognition cognitive paradigms.
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Antagonistas de los Receptores Histamínicos H3 , Receptores Histamínicos H3 , Ratas , Humanos , Animales , Histamina , Agonismo Inverso de Drogas , Receptores Histamínicos H3/metabolismo , Simulación del Acoplamiento Molecular , Agonistas de los Receptores Histamínicos/farmacología , Agonistas de los Receptores Histamínicos/metabolismo , Esteroides , Microsomas Hepáticos/metabolismo , Antagonistas de los Receptores Histamínicos H3/farmacología , Antagonistas de los Receptores HistamínicosRESUMEN
During optimization of a previously identified lead compound, attempts were made to optimize the reactive indole structural element, the suboptimal metabolic stability, as well as the low kinetic solubility. It was concluded that the indole was important for in vitro activity. With the aim of further improvements, more thorough modifications were also carried out. As a result, a new chemotype (the azetidinespirochromone family) was identified, which proved to be 1 order of magnitude less lipophilic retaining the same high level of in vitro potency as the lead series itself, however, with improved metabolic stability and kinetic solubility. Compound 53 showed the most balanced physicochemical and pharmacological profile with significant in vivo efficacy in the scopolamine-induced amnesia test. Based on these promising results, cognitive enhancement through the positive modulation of α7 nAChRs appears to be a viable approach. Compound 53 was selected to be a preclinical development candidate (as RGH-560).
Asunto(s)
Receptores Nicotínicos , Receptor Nicotínico de Acetilcolina alfa 7 , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Regulación Alostérica , Receptores Nicotínicos/metabolismo , Indoles/farmacologíaRESUMEN
For a long time, oxytocin has been thought to have a generally positive effect on social cognition and prosocial behavior; however, recent results suggested that oxytocin has beneficial effects only under certain conditions. The aim of the present study was to explore potential associations between social competence and the effect of intranasal oxytocin on the social behavior of laboratory beagle dogs. We expected oxytocin treatment to have a more pronounced positive effect on dogs with lower baseline performance in a social test battery. Thirty-six adult dogs of both sexes received 32 IU intranasal oxytocin and physiological saline (placebo) treatment in a double-blind, cross-over design, with 17-20 days between the two sessions. Forty minutes after the treatment, dogs participated in a social test battery consisting of eight situations. The situations were carried out within one session and took 20-30 min to complete. Principal component analysis on the coded behaviors identified four components (Willingness to interact, Preference for social contact, Non-aversive response to nonsocial threat, and Non-aversive response to social threat). The subjects' behavior during the placebo condition was used to assess their baseline performance. We found that oxytocin treatment had a differential effect on the behavior depending on the baseline performance of the individuals in all components, but only two treatment × baseline performance interactions remained significant in a less sensitive analysis. In accordance with our hypothesis, oxytocin administration increased dogs' contact seeking and affiliative behaviors toward humans but only for those with low baseline performance. Dogs with low baseline performance also showed significantly more positive (friendly) reactions to social threat after oxytocin administration than after placebo, while for dogs with high baseline performance, oxytocin administration led to a more negative (fearful) reaction. These results indicate that similar to those on humans, the effects of oxytocin on dogs' social behavior are not universally positive but are constrained by individual characteristics and the context. Nevertheless, oxytocin administration has the potential to improve the social behavior of laboratory beagle dogs that are socially less proficient when interacting with humans, which could have both applied and animal welfare implications.
RESUMEN
The human mu rhythm has been suggested to represent an important function in information processing. Rodent homologue rhythms have been assumed though no study has investigated them from the cognitive aspect yet. As voluntary goal-directed movements induce the desynchronization of mu rhythm, we aimed at exploring whether the response-related brain activity during the touchscreen visual discrimination (VD) task is suitable to detect sensorimotor rhythms and their change under cognitive impairment. Different doses of scopolamine or MK-801 were injected subcutaneously to rats, and epidural electroencephalogram (EEG) was recorded during task performance. Arciform ~ 10 Hz oscillations appeared during visual processing, then two characteristic alpha/beta desynchronization-resynchronization patterns emerged mainly above the sensorimotor areas, serving presumably different motor functions. Beyond causing cognitive impairment, both drugs supressed the touch-related upper alpha (10-15 Hz) reactivity for desynchronization. Reaction time predominantly correlated positively with movement-related alpha and beta power both in normal and impaired conditions. These results support the existence of a mu homologue rodent rhythm whose upper alpha component appeared to be modulated by cholinergic and glutamatergic mechanisms and its power change might indicate a potential EEG correlate of processing speed. The VD task can be utilized for the investigation of sensorimotor rhythms in rats.
Asunto(s)
Maleato de Dizocilpina , Escopolamina , Animales , Ritmo beta , Maleato de Dizocilpina/farmacología , Electroencefalografía , Movimiento , Ratas , Escopolamina/farmacología , Percepción VisualRESUMEN
The histamine H3 receptor is a favourable target for the treatment of cognitive deficits. Here we report the in vitro and in vivo profile of RGH-235, a new potent, selective, and orally active H3 receptor antagonist/inverse agonist developed by Gedeon Richter Plc. Radioligand binding and functional assays were used for in vitro profiling. Procognitive efficacy was investigated in rodent cognitive tests, in models of attention deficit hyperactive disorder (ADHD) and in cognitive tests of high translational value (rat touch screen visual discrimination test, primate fixed-foreperiod visual reaction time task). Results were supported by pharmacokinetic studies, neurotransmitter release, sleep EEG and dipsogenia. RGH-235 displayed high affinity to H3 receptors (Ki = 3.0-9.2 nM, depending on species), without affinity to H1, H2 or H4 receptors and >100 other targets. RGH-235 was an inverse agonist ([35S] GTPγS binding) and antagonist (pERK1/2 ELISA), showing favourable kinetics, inhibition of the imetit-induced dipsogenia and moderate effects on sleep-wake EEG. RGH-235 stimulated neurotransmitter release both in vitro and in vivo. RGH-235 was active in spontaneously hypertensive rats (SHR), generally considered as a model of ADHD, and revealed a robust pro-cognitive profile both in rodent and primate tests (in 0.3-1 mg/kg) and in models of high translational value (e.g. in a rodent touch screen test and in non-human primates). The multiple and convergent procognitive effects of RGH-235 support the view that beneficial cognitive effects can be linked to antagonism/inverse agonism of H3 receptors.
Asunto(s)
Receptores Histamínicos H3 , Animales , Cognición , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Histamina/farmacología , Agonistas de los Receptores Histamínicos/metabolismo , Ratas , Receptores Histamínicos H3/metabolismoRESUMEN
Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8−9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics.
Asunto(s)
Antipsicóticos , Clozapina , Animales , Antipsicóticos/farmacología , Clozapina/farmacología , Hipocampo , Plasticidad Neuronal , Corteza Prefrontal , Ratas , Ratas Wistar , Risperidona/farmacologíaRESUMEN
Cholinergic neuromodulation is known to play a key role in visual working memory (VWM) - keeping relevant stimulus representations available for cognitive processes for short time periods (up to a few minutes). Despite the growing body of evidence on how the neural and cognitive mechanisms of VWM dynamically change over retention time, there is mixed evidence available on cholinergic effects as a function of VWM delay period in non-human primates. Using the delayed matching to sample VWM task in rhesus macaques (N = 6), we aimed to characterize VWM maintenance in terms of performance changes as a function of delay duration (across a wide range of delays from 1 to 76 s). Then, we studied how cholinergic neuromodulation influences VWM maintenance using the muscarinic receptor antagonist scopolamine administered alone as transient amnestic treatment, and in combination with two doses of the acetylcholinesterase inhibitor donepezil, a widely used Alzheimer's medication probing for the reversal of scopolamine-induced impairments. Results indicate that scopolamine-induced impairments of VWM maintenance are delay-dependent and specifically affect the 15-33 s time range, suggesting that scopolamine worsens the normal decay of VWM with the passage of time. Donepezil partially rescued the observed scopolamine-induced impairments of VWM performance. These results provide strong behavioral evidence for the role of increased cholinergic tone and muscarinic neuromodulation in the maintenance of VWM beyond a few seconds, in line with our current knowledge on the role of muscarinic acetylcholine receptors in sustained neural activity during VWM delay periods.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Memoria a Corto Plazo/efectos de los fármacos , Antagonistas Muscarínicos/farmacología , Desempeño Psicomotor/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Inhibidores de la Colinesterasa/administración & dosificación , Demencia/tratamiento farmacológico , Modelos Animales de Enfermedad , Donepezilo/farmacología , Macaca mulatta , Masculino , Antagonistas Muscarínicos/administración & dosificación , Reconocimiento Visual de Modelos/efectos de los fármacos , Escopolamina/farmacología , Factores de TiempoRESUMEN
Dopamine (DA), as one of the major neurotransmitters in the central nervous system (CNS) and periphery, exerts its actions through five types of receptors which belong to two major subfamilies such as D1-like (i.e., D1 and D5 receptors) and D2-like (i.e., D2, D3 and D4) receptors. Dopamine D3 receptor (D3R) was cloned 30 years ago, and its distribution in the CNS and in the periphery, molecular structure, cellular signaling mechanisms have been largely explored. Involvement of D3Rs has been recognized in several CNS functions such as movement control, cognition, learning, reward, emotional regulation and social behavior. D3Rs have become a promising target of drug research and great efforts have been made to obtain high affinity ligands (selective agonists, partial agonists and antagonists) in order to elucidate D3R functions. There has been a strong drive behind the efforts to find drug-like compounds with high affinity and selectivity and various functionality for D3Rs in the hope that they would have potential treatment options in CNS diseases such as schizophrenia, drug abuse, Parkinson's disease, depression, and restless leg syndrome. In this review, we provide an overview and update of the major aspects of research related to D3Rs: distribution in the CNS and periphery, signaling and molecular properties, the status of ligands available for D3R research (agonists, antagonists and partial agonists), behavioral functions of D3Rs, the role in neural networks, and we provide a summary on how the D3R-related drug research has been translated to human therapy.
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Investigación Biomédica , Enfermedades del Sistema Nervioso Central/metabolismo , Neuronas/metabolismo , Receptores de Dopamina D3/metabolismo , Investigación Biomédica Traslacional , Animales , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Receptores de Dopamina D3/antagonistas & inhibidores , Receptores de Dopamina D3/químicaRESUMEN
Our previous scaffold-hopping attempts resulted in dihydropyrazino-benzimidazoles as metabotropic glutamate receptor-2 (mGluR2) positive allosteric modulators (PAMs) with suboptimal drug-like profiles. Here, we report an alternative fragment-based optimization strategy applied on the new dihydropyrazino-benzimidazolone scaffold. Analyzing published high-affinity mGluR2 PAMs, we used a pharmacophore-guided approach to identify suitable growing vectors and optimize the scaffold in these directions. This strategy resulted in a new fragment like lead (34) with improved druglike properties that were translated to sufficient pharmacokinetics and validated proof-of-concept studies in migraine. Gratifyingly, compound 34 showed reasonable activity in the partial infraorbital nerve ligation, a migraine disease model that might open this indication for mGluR2 PAMs.
Asunto(s)
Bencimidazoles/uso terapéutico , Agonistas de Aminoácidos Excitadores/uso terapéutico , Trastornos Migrañosos/tratamiento farmacológico , Pirazinas/uso terapéutico , Receptores de Glutamato Metabotrópico/agonistas , Animales , Bencimidazoles/síntesis química , Bencimidazoles/farmacocinética , Agonistas de Aminoácidos Excitadores/síntesis química , Agonistas de Aminoácidos Excitadores/farmacocinética , Masculino , Estructura Molecular , Prueba de Estudio Conceptual , Pirazinas/síntesis química , Pirazinas/farmacocinética , Ratas Wistar , Relación Estructura-ActividadRESUMEN
HTS campaign of the corporate compound collection resulted in a novel, oxalic acid diamide scaffold of α7 nACh receptor positive allosteric modulators. During the hit expansion, several derivatives, such as 4, 11, 17 demonstrated not only high in vitro potency, but also in vivo efficacy in the mouse place recognition test. The advanced hit molecule 11 was further optimized by the elimination of the putatively mutagenic aromatic-amine building block that resulted in a novel, aminomethylindole compound family. The most balanced physico-chemical and pharmacological profile was found in case of compound 55. Docking study revealed an intersubunit binding site to be the most probable for our compounds. 55 demonstrated favorable cognitive enhancing profile not only in scopolamine-induced amnesia (place recognition test in mice) but also in natural forgetting (novel object recognition test in rats). Compound 55 was, furthermore, active in a cognitive paradigm of high translational value, namely in the rat touch screen visual discrimination test. Therefore, 55 was selected as a lead compound for further optimization. Based on the obtained favorable results, the invented aminomethylindole cluster may provide a viable approach for cognitive enhancement through positive allosteric modulation of α7 nAChRs.
Asunto(s)
Amidas/farmacología , Descubrimiento de Drogas , Ensayos Analíticos de Alto Rendimiento , Ácido Oxálico/farmacología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Regulación Alostérica/efectos de los fármacos , Amidas/síntesis química , Amidas/química , Animales , Relación Dosis-Respuesta a Droga , Humanos , Masculino , Estructura Molecular , Ácido Oxálico/síntesis química , Ácido Oxálico/química , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
The paper focuses on the scaffold hopping-based discovery and characterization of novel nicotinic alpha 7 receptor positive modulator (α7 nAChR PAM) ligands around the reference molecule (A-867744). First, substantial efforts were carried out to assess the importance of the various pharmacophoric elements on the in vitro potency (SAR evaluation) by chemical modifications. Subsequently, several new derivatives with versatile, heteroaromatic central cores were synthesized and characterized. A promising, pyrazole-containing new chemotype with good physicochemical and in vitro parameters was identified. Retrospective analysis based on homology modeling was also carried out. Besides its favorable in vitro characteristics, the most advanced derivative 69 also showed in vivo efficacy in a rodent model of cognition (scopolamine-induced amnesia in the mouse place recognition test) and acceptable pharmacokinetic properties. Based on the in vivo data, the resulting molecule with advanced drug-like characteristics has the possibility to improve cognitive performance in a biologically relevant dose range, further strengthening the view of the supportive role of α7 nACh receptors in the cognitive processes.
Asunto(s)
Descubrimiento de Drogas , Agonistas Nicotínicos/farmacología , Pirazoles/farmacología , Administración Oral , Regulación Alostérica/efectos de los fármacos , Amnesia/inducido químicamente , Amnesia/tratamiento farmacológico , Amnesia/metabolismo , Animales , Relación Dosis-Respuesta a Droga , Células HEK293 , Humanos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Microsomas Hepáticos/química , Microsomas Hepáticos/metabolismo , Estructura Molecular , Agonistas Nicotínicos/administración & dosificación , Agonistas Nicotínicos/metabolismo , Pirazoles/administración & dosificación , Pirazoles/metabolismo , Ratas , Ratas Wistar , Escopolamina , Relación Estructura-Actividad , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
The most dominant hypotheses for the pathogenesis of schizophrenia have focused primarily upon hyperfunctional dopaminergic and hypofunctional glutamatergic neurotransmission in the central nervous system. The therapeutic efficacy of all atypical antipsychotics is explained in part by antagonism of the dopaminergic neurotransmission, mainly by blockade of D(2) dopamine receptors. N-methyl-D-aspartate (NMDA) receptor hypofunction in schizophrenia can be reversed by glycine transporter type-1 (GlyT-1) inhibitors, which regulate glycine concentrations at the vicinity of NMDA receptors. Combined drug administration with D(2) dopamine receptor blockade and activation of hypofunctional NMDA receptors may be needed for a more effective treatment of positive and negative symptoms and the accompanied cognitive deficit in schizophrenia. To investigate this type of combined drug administration, rats were treated with the atypical antipsychotic risperidone together with the GlyT-1 inhibitor Org-24461. Brain microdialysis was applied in the striatum of conscious rats and determinations of extracellular dopamine, DOPAC, HVA, glycine, glutamate, and serine concentrations were carried out using HPLC/electrochemistry. Risperidone increased extracellular concentrations of dopamine but failed to influence those of glycine or glutamate measured in microdialysis samples. Org-24461 injection reduced extracellular dopamine concentrations and elevated extracellular glycine levels but the concentrations of serine and glutamate were not changed. When risperidone and Org-24461 were added in combination, a decrease in extracellular dopamine concentrations was accompanied with sustained elevation of extracellular glycine levels. Interestingly, the extracellular concentrations of glutamate were also enhanced. Our data indicate that coadministration of an antipsychotic with a GlyT-1 inhibitor may normalize hypofunctional NMDA receptor-mediated glutamatergic neurotransmission with reduced dopaminergic side effects characteristic for antipsychotic medication.
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Cuerpo Estriado/efectos de los fármacos , Dopamina/metabolismo , Espacio Extracelular/metabolismo , Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Glicina/metabolismo , Risperidona/farmacología , Sarcosina/análogos & derivados , Animales , Cuerpo Estriado/metabolismo , Masculino , Microdiálisis , Unión Proteica , Ratas , Sarcosina/farmacologíaRESUMEN
Prediction of movement intentions from electromyographic (EMG) signals is typically performed with a pattern recognition approach, wherein a short dataframe of raw EMG is compressed into an instantaneous feature-encoding that is meaningful for classification. However, EMG signals are time-varying, implying that a frame-wise approach may not sufficiently incorporate temporal context into predictions, leading to erratic and unstable prediction behavior. OBJECTIVE: We demonstrate that sequential prediction models and, specifically, temporal convolutional networks are able to leverage useful temporal information from EMG to achieve superior predictive performance. METHODS: We compare this approach to other sequential and frame-wise models predicting 3 simultaneous hand and wrist degrees-of-freedom from 2 amputee and 13 non-amputee human subjects in a minimally constrained experiment. We also compare these models on the publicly available Ninapro and CapgMyo amputee and non-amputee datasets. RESULTS: Temporal convolutional networks yield predictions that are more accurate and stable than frame-wise models, especially during inter-class transitions, with an average response delay of 4.6 ms and simpler feature-encoding. Their performance can be further improved with adaptive reinforcement training. SIGNIFICANCE: Sequential models that incorporate temporal information from EMG achieve superior movement prediction performance and these models allow for novel types of interactive training. CONCLUSIONS: Addressing EMG decoding as a sequential modeling problem will lead to enhancements in the reliability, responsiveness, and movement complexity available from prosthesis control systems.
Asunto(s)
Amputados , Miembros Artificiales , Electromiografía , Mano , Humanos , Movimiento , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The social approach and social novelty tests utilizing the three-chamber apparatus are widely accepted to measure social behavior of rodents. The LABORAS™ system offers a possibility to assess sociability of mice in a reliable and objective manner. NEW METHOD: We assessed the capability of the LABORAS™ sociability cage and algorithm (2.6.6) to detect social behaviors in mice. Furthermore, we investigated whether the system is able to detect various levels of sociability due to genetic background or after pharmacological treatments. RESULTS: By comparing manual scoring with various detection zone settings of the automated registration, the most fitting algorithm with a detection zone radius of 90â¯mm was identified. When different strains were investigated, C57Bl/6â¯J and NMRI mice proved to be social, while CD1 mice were found asocial. The system was able to detect the sociability increasing effect of R-baclofen (0.5â¯mg/kg i.p.) and oxytocin (12â¯ng i.c.v.) in asocial CD1 mice. The negative control PCP impaired social behavior of C57Bl/6â¯J mice (1â¯mg/kg i.p.) and increased social avoidance in CD1 mice (0.3â¯mg/kg i.p.). COMPARISON WITH EXISTING METHOD(S): This setup, in contrast to video frame analysis softwares, determines signal changes caused by movements of rodents allowing accurate detection and analysis of trajectories. Parallel automated measurements also allow replacing time and labor intensive, highly subjective human observational work. CONCLUSIONS: The set-up provides a fast and reliable method to examine social behavior of mice in the three-chamber apparatus. The system is capable of detecting pro or antisocial activity of pharmacological agents.