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2.
J Addict Med ; 13(1): 7-22, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30096077

RESUMO

: Topiramate is a non-benzodiazepine anticonvulsant medication with multi-faceted pharmacologic action. It has emerged as an efficacious pharmacotherapeutic option for the treatment of addiction, especially alcohol use disorder (AUD). We present a broad narrative review of the putative mechanism of action and clinical utility of topiramate with regard to AUD and other substance use disorders. Collective evidence suggests topiramate is an effective treatment option in AUD, with notable efficacy in reducing harmful drinking patterns in AUD. Though not currently approved by the United States Food and Drug Administration for the indication of AUD, topiramate should be considered as a pharmacological treatment option with high utility among AUD patients. Early pharmacogenetic studies raise the intriguing possibility of identifying patients likely to respond to topiramate using genetic testing, and initial studies show that topiramate may also be useful in treating cocaine use disorder, smoking cessation and behavioral addictions. However, further research is needed in all these areas.


Assuntos
Transtornos Relacionados ao Uso de Álcool/tratamento farmacológico , Comportamento Aditivo/tratamento farmacológico , Transtornos Relacionados ao Uso de Cocaína/tratamento farmacológico , Neurotransmissores/farmacologia , Fumar/tratamento farmacológico , Topiramato/farmacologia , Humanos , Neurotransmissores/efeitos adversos , Neurotransmissores/farmacocinética , Topiramato/efeitos adversos , Topiramato/farmacocinética
3.
Behav Brain Res ; 359: 671-685, 2019 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-30267715

RESUMO

Recent preclinical studies point to muscarinic and GABAB receptors as novel therapeutic targets for the treatment of schizophrenia. This study was aimed to assess the role of muscarinic and GABAB receptor interactions in animal models of schizophrenia, using positive allosteric modulators (PAMs) of GABAB receptor (GS39783), muscarinic M4 (VU0152100) and M5 (VU0238429) receptor, and partial allosteric agonist of M1 receptor (VU0357017). DOI-induced head twitches, social interaction and novel object recognition tests were used as the models of schizophrenia. Analyses of DOI-induced increases in sEPSCs (spontaneous excitatory postsynaptic currents) were performed as complementary experiments to the DOI-induced head twitch studies. Haloperidol-induced catalepsy and the rotarod test were used to examine the adverse effects of the drugs. All three activators of muscarinic receptors were active in DOI-induced head twitches. When administered together with GS39783 in subeffective doses, only the co-administration of VU0152100 and GS39783 was effective. The combination also reduced the frequency but not the amplitude of DOI-induced sEPSCs. Neither VU0357017 nor VU0238429 were active in social interaction test when given alone, and also the combination of VU0152100 and GS39783 failed to reverse MK-801-induced deficits observed in this test. All muscarinic activators when administered alone or in combination with GS39783 reversed the MK-801-induced disruption of memory in the novel object recognition test, and their actions were blocked by specific antagonists. None of the tested compounds or their combinations influenced the motor coordination of the animals. The compounds had no effect on haloperidol-induced catalepsy and did not induce catalepsy when administered alone. Pharmacokinetic analysis confirmed lack of possible drug-drug interactions after combined administration of GS39783 with VU0357017 or VU0152100; however, when the drug was co-administered with VU0238429 its ability to pass the blood-brain barrier slightly decreased, suggesting potential drug-drug interactions. Our data show that modulation of cholinergic and GABAergic systems can potentially be beneficial in the treatment of the positive and cognitive symptoms of schizophrenia without inducing the adverse effects typical for presently used antipsychotics.


Assuntos
Antipsicóticos/farmacologia , Neurotransmissores/farmacologia , Receptores de GABA-B/metabolismo , Receptores Muscarínicos/metabolismo , Esquizofrenia/tratamento farmacológico , Regulação Alostérica , Animais , Antipsicóticos/farmacocinética , Benzamidas/farmacocinética , Benzamidas/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Ciclopentanos/farmacocinética , Ciclopentanos/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Indóis/farmacocinética , Indóis/farmacologia , Masculino , Camundongos , Neurotransmissores/farmacocinética , Piridinas/farmacocinética , Piridinas/farmacologia , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Esquizofrenia/metabolismo , Tiofenos/farmacocinética , Tiofenos/farmacologia
4.
J Comp Neurol ; 526(3): 439-466, 2018 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-29063593

RESUMO

At the beginning of the 20th century it was suggested that a complex group of nuclei in the avian posterior ventral telencephalon is comparable to the mammalian amygdala. Subsequent findings, however, revealed that most of these structures share premotor characteristics, while some indeed constitute the avian amygdala. These developments resulted in 2004 in a change of nomenclature of these nuclei, which from then on were named arcopallial or amygdala nuclei and referred to as the arcopallium/amygdala complex. The structural basis for the similarities between avian and mammalian arcopallial and amygdala subregions is poorly understood. Therefore, we analyzed binding site densities for glutamatergic AMPA, NMDA and kainate, GABAergic GABAA , muscarinic M1 , M2 and nicotinic acetylcholine (nACh; α4 ß2 subtype), noradrenergic α1 and α2 , serotonergic 5-HT1A and dopaminergic D1/5 receptors using quantitative in vitro receptor autoradiography combined with a detailed analysis of the cyto- and myelo-architecture. Our approach supports a segregation of the pigeon's arcopallium/amygdala complex into the following subregions: the arcopallium anterius (AA), the arcopallium ventrale (AV), the arcopallium dorsale (AD), the arcopallium intermedium (AI), the arcopallium mediale (AM), the arcopallium posterius (AP), the nucleus posterioris amygdalopallii pars basalis (PoAb) and pars compacta (PoAc), the nucleus taeniae amgygdalae (TnA) and the area subpallialis amygdalae (SpA). Some of these subregions showed further subnuclei and each region of the arcopallium/amygdala complex are characterized by a distinct multi-receptor density expression. Here we provide a new detailed map of the pigeon's arcopallium/amygdala complex and compare the receptor architecture of the subregions to their possible mammalian counterparts.


Assuntos
Tonsila do Cerebelo/metabolismo , Columbidae/anatomia & histologia , Receptores de Neurotransmissores/metabolismo , Tonsila do Cerebelo/efeitos dos fármacos , Animais , Autorradiografia , Columbidae/metabolismo , Neurotransmissores/farmacocinética , Ligação Proteica/efeitos dos fármacos , Ligação Proteica/fisiologia , Trítio/farmacocinética
5.
Brain Struct Funct ; 223(4): 1637-1666, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29188378

RESUMO

The human amygdala consists of subdivisions contributing to various functions. However, principles of structural organization at the cellular and molecular level are not well understood. Thus, we re-analyzed the cytoarchitecture of the amygdala and generated cytoarchitectonic probabilistic maps of ten subdivisions in stereotaxic space based on novel workflows and mapping tools. This parcellation was then used as a basis for analyzing the receptor expression for 15 receptor types. Receptor fingerprints, i.e., the characteristic balance between densities of all receptor types, were generated in each subdivision to comprehensively visualize differences and similarities in receptor architecture between the subdivisions. Fingerprints of the central and medial nuclei and the anterior amygdaloid area were highly similar. Fingerprints of the lateral, basolateral and basomedial nuclei were also similar to each other, while those of the remaining nuclei were distinct in shape. Similarities were further investigated by a hierarchical cluster analysis: a two-cluster solution subdivided the phylogenetically older part (central, medial nuclei, anterior amygdaloid area) from the remaining parts of the amygdala. A more fine-grained three-cluster solution replicated our previous parcellation including a laterobasal, superficial and centromedial group. Furthermore, it helped to better characterize the paralaminar nucleus with a molecular organization in-between the laterobasal and the superficial group. The multimodal cyto- and receptor-architectonic analysis of the human amygdala provides new insights into its microstructural organization, intersubject variability, localization in stereotaxic space and principles of receptor-based neurochemical differences.


Assuntos
Tonsila do Cerebelo/metabolismo , Mapeamento Encefálico , Vias Neurais/metabolismo , Receptores de Neurotransmissores/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/efeitos dos fármacos , Autopsia , Autorradiografia , Feminino , Lateralidade Funcional , Humanos , Processamento de Imagem Assistida por Computador , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Vias Neurais/diagnóstico por imagem , Neurotransmissores/farmacocinética , Trítio/farmacocinética
6.
J Pain ; 18(6): 726-738, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28188907

RESUMO

Most previous transient receptor potential vanilloid subtype 1 (TRPV1) antagonist programs have been put on hold, mainly because of on-target adverse events: hyperthermia and impaired noxious heat sensation. NEO6860 is a TRPV1 antagonist, blocking capsaicin activation of the target, with little or no effect against pH or heat activation. The hypothesis is that this pharmacological profile will translate into analgesia without undesired effects on the body temperature or heat-pain threshold. This phase I, double blind, placebo controlled, ascending dose study, included 64 subjects. Pharmacodynamics (intradermal capsaicin test) was explored. The study was comprised of 6 dose levels (50, 100, 200, 400, 800, and 1,200 mg) and 2 doses of 500 mg, 12 hours apart. NEO6860 was rapidly absorbed and systemic exposure increases were less than dose proportional. Median time of maximum observed plasma concentration values ranged from 2 to 3 hours. The mean apparent plasma terminal elimination half-life was between 4 and 8 hours. No significant food-effect or gender-effect was observed. The most frequently reported events were feeling hot, headache, paresthesia, nausea, and dizziness. Single oral doses of up to 800 mg and two 500-mg doses administered 12 hours apart of NEO6860 were well tolerated in this study. Unlike other TRPV1 antagonists, no clinically significant increase in temperature or heat pain threshold/tolerance was noted despite thorough and specific monitoring of these parameters. At all doses, most subjects reported a sensation of "feeling hot," with a rapid onset and transient. NEO6860 showed an improvement in the pharmacodynamics parameters (evoked pain and secondary hyperalgesia) at 3 and 8 hours post NEO6860 dosing. PERSPECTIVE: This first in human study on NEO6860, showed that an antagonist of TRPV1, blocking only the activation by capsaicin has been identified. This finding paves the way for the development of a new powerful analgesic for many pain conditions, without the fear of the side effects observed with previous TRPV1 antagonists.


Assuntos
Neurotransmissores/efeitos adversos , Neurotransmissores/farmacocinética , Canais de Cátion TRPV/antagonistas & inibidores , Administração Oral , Adulto , Área Sob a Curva , Temperatura Corporal/efeitos dos fármacos , Capsaicina/farmacologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Jejum , Feminino , Humanos , Masculino , Limiar da Dor/efeitos dos fármacos , Dados Preliminares
7.
Am J Physiol Gastrointest Liver Physiol ; 309(10): G816-25, 2015 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-26336928

RESUMO

Pituitary adenylate cyclase-activating peptide (PACAP) is expressed within the gastroenteric system, where it has profound physiological effects. PACAP was shown to regulate food intake and thermogenesis centrally; however, PACAP peripheral regulation of appetite and feeding behavior is unknown. Therefore, we studied PACAP's effect on appetite and food intake control by analyzing feeding behavior and metabolic hormones in PAC1-deficient (PAC1-/-) and age-matched wild-type (WT) mice intraperitoneally injected with PACAP1-38 or PACAP1-27 before the dark phase of feeding. Food intake and feeding behavior were analyzed using the BioDAQ system. Active ghrelin, glucagon-like peptide-1 (GLP-1), leptin, peptide YY, pancreatic polypeptide, and insulin were measured following PACAP1-38 administration in fasted WT mice. PACAP1-38/PACAP1-27 injected into WT mice significantly decreased in a dose-dependent manner cumulative food intake and reduced bout and meal feeding parameters. Conversely, PACAP1-38 injected into PAC1-/- mice failed to significantly change food intake. Importantly, PACAP1-38 reduced plasma levels of active ghrelin compared with vehicle in WT mice. In PAC1-/- mice, fasting levels of active ghrelin, GLP-1, insulin, and leptin and postprandial levels of active ghrelin and insulin were significantly altered compared with levels in WT mice. Therefore, PAC1 is a novel regulator of appetite/satiety. PACAP1-38/PACAP1-27 significantly reduced appetite and food intake through PAC1. In PAC1-/- mice, the regulation of anorexigenic/orexigenic hormones was abolished, whereas active ghrelin remained elevated even postprandially. PACAP significantly reduced active ghrelin in fasting conditions. These results establish a role for PACAP via PAC1 in the peripheral regulation of appetite/satiety and suggest future studies to explore a therapeutic use of PACAP or PAC1 agonists for obesity treatment.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Grelina , Leptina/metabolismo , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Receptores de Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/metabolismo , Animais , Apetite/efeitos dos fármacos , Regulação do Apetite/fisiologia , Relação Dose-Resposta a Droga , Comportamento Alimentar , Trato Gastrointestinal/metabolismo , Grelina/antagonistas & inibidores , Grelina/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Injeções Intraperitoneais , Masculino , Camundongos , Modelos Animais , Neurotransmissores/administração & dosagem , Neurotransmissores/farmacocinética , Peptídeo YY/sangue , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/administração & dosagem , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase/farmacocinética
8.
Artigo em Inglês | MEDLINE | ID: mdl-26051684

RESUMO

Cinnarizine is a piperazine derivative with antihistaminic, antiserotonergic, antidopaminergic, and calcium channel-blocking activities. A comprehensive profile was performed on cinnarizine including its description and the different methods of analysis. The 1H NMR and 13C one- and two-dimensional NMR methods were used. In addition, infrared and mass spectral analyses were performed which all confirmed the structure of cinnarizine.


Assuntos
Bloqueadores dos Canais de Cálcio/química , Cinarizina/química , Neurotransmissores/química , Animais , Bloqueadores dos Canais de Cálcio/farmacocinética , Bloqueadores dos Canais de Cálcio/farmacologia , Química Farmacêutica , Cinarizina/farmacocinética , Cinarizina/farmacologia , Antagonistas de Dopamina/química , Estabilidade de Medicamentos , Antagonistas dos Receptores Histamínicos H1/química , Humanos , Estrutura Molecular , Neurotransmissores/farmacocinética , Neurotransmissores/farmacologia , Antagonistas da Serotonina/química , Tecnologia Farmacêutica/métodos
9.
J Med Chem ; 58(8): 3500-11, 2015 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-25799373

RESUMO

Neuroactive steroids (NASs) have been shown to impact central nervous system (CNS) function through positive allosteric modulation of the GABA(A) receptor (GABA(A)-R). Herein we report the effects on the activity and pharmacokinetic properties of a series of nor-19 pregnanolone analogues bearing a heterocyclic substituent at C-21. These efforts resulted in the identification of SGE-516, a balanced synaptic/extrasynaptic GABA(A) receptor modulator, and SGE-872, a selective extrasynaptic GABA(A) receptor modulator. Both molecules possess excellent druglike properties, making them advanced leads for oral delivery of GABA(A) receptor modulators.


Assuntos
Neurotransmissores/química , Neurotransmissores/farmacologia , Pregnanolona/análogos & derivados , Pregnanolona/farmacologia , Receptores de GABA/metabolismo , Regulação Alostérica/efeitos dos fármacos , Animais , Humanos , Camundongos , Neurotransmissores/farmacocinética , Pregnanolona/farmacocinética , Ratos , Relação Estrutura-Atividade
10.
Eur Neuropsychopharmacol ; 25(4): 544-56, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25638027

RESUMO

Triple reuptake inhibitors that block dopamine transporters (DATs), norepinephrine transporters (NETs), and serotonin transporters (SERTs) are being developed as a new class of antidepressants that might have better efficacy and fewer side effects than traditional antidepressants. In this study, we performed in vitro binding and uptake assays as well as in vivo behavioural tests to assess the pharmacological properties and antidepressant-like efficacy of Yuanzhi-1. In vitro, Yuanzhi-1 had a high affinity for SERTs, NETs, and DATs prepared from rat brain tissue (Ki=3.95, 4.52 and 0.87nM, respectively) and recombinant cells (Ki=2.87, 6.86 and 1.03nM, respectively). Moreover, Yuanzhi-1 potently inhibited the uptake of serotonin (5-hydroxytryptamine; 5-HT), norepinephrine (NE) and dopamine (DA) into rat brain synaptosomes (Ki=2.12, 4.85 and 1.08nM, respectively) and recombinant cells (Ki=1.65, 5.32 and 0.68nM, respectively). In vivo, Yuanzhi-1 decreased immobility in a dose-dependent manner, which was shown among rats via the forced-swim test (FST) and mice via the tail-suspension test (TST). The results observed in the behavioural tests did not appear to result from the stimulation of locomotor activity. Repeated Yuanzhi-1 treatment (2.5, 5 or 10mg/kg) significantly reversed depression-like behaviours in chronically stressed rats, including reduced sucrose preference, decreased locomotor activity, and prolonged time to begin eating. Furthermore, in vivo microdialysis studies showed that 5- and 10-mg/kg administrations of Yuanzhi-1 significantly increased the extracellular concentrations of 5-HT, NE and DA in the frontal cortices of freely moving rats. Therefore, Yuanzhi-1 might represent a novel triple reuptake inhibitor and possess antidepressant-like activity.


Assuntos
Antidepressivos/farmacologia , Medicamentos de Ervas Chinesas/farmacologia , Inibidores da Captação de Neurotransmissores/farmacologia , Sinaptossomos/efeitos dos fármacos , Animais , Citalopram/farmacocinética , Corpo Estriado/citologia , Depressão/tratamento farmacológico , Modelos Animais de Doenças , Preferências Alimentares/efeitos dos fármacos , Lobo Frontal/citologia , Humanos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Neurotransmissores/farmacocinética , Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo , Ligação Proteica/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Saponinas/farmacologia , Saponinas/uso terapêutico , Sacarose/administração & dosagem , Trítio/farmacocinética
11.
Brain Struct Funct ; 220(1): 205-19, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24126835

RESUMO

Recently, two extrastriate visual areas on the posterior fusiform gyrus, areas FG1 and FG2, were identified based on cytoarchitectonical criteria (Caspers et al. in Brain Struct Funct 218:511-526, 2013a). They are located within the object-related ventral visual stream at the transition between early and higher-order (category-specific) visual areas. FG2 has a topographical position which is best comparable to the face or visual word-form recognition area. However, the precise function of FG2 is presently unknown. Since transmitter receptors are key molecules of neurotransmission, we analysed the regional and laminar distribution of 15 different receptor binding sites by means of quantitative in vitro receptor autoradiography. Significant differences between receptor densities of both areas were found for NMDA, GABAB, M3, nicotinic α4/ß2 and 5-HT1A receptors as well as for GABAA associated benzodiazepine binding sites. These results support the cytoarchitectonic segregation of FG1 and FG2 into two distinct cortical areas. In addition, principal component and hierarchical cluster analyses of the multireceptor data of both fusiform areas and 24 visual, auditory, somatosensory and multimodal association areas not only revealed the typical receptor architectonic characteristics of visual areas for FG1 and FG2, but also suggest their putative function as object recognition regions due to the similarity of their receptor fingerprints with those of areas of the ventral visual stream. Furthermore, FG1 and FG2 build a cluster with the multimodal association areas of the inferior parietal lobule. This underlines their hierarchically high position in the visual system of the human cerebral cortex.


Assuntos
Mapeamento Encefálico , Receptores de Neurotransmissores/metabolismo , Lobo Temporal/anatomia & histologia , Lobo Temporal/metabolismo , Idoso , Autorradiografia , Análise por Conglomerados , Processamento Eletrônico de Dados , Face , Feminino , Humanos , Masculino , Neurotransmissores/farmacocinética , Mudanças Depois da Morte , Lobo Temporal/efeitos dos fármacos , Trítio/farmacocinética
12.
Actas esp. psiquiatr ; 42(5): 234-241, sept.-oct. 2014.
Artigo em Espanhol | IBECS | ID: ibc-128690

RESUMO

Actualmente se considera que tanto los síntomas positivos como en negativos de la esquizofrenia podrían deberse a una hipofunción glutamatérgica que tendría como consecuencia la alteración de la actividad de la neurotransmisión dopaminérgica. Concretamente, podría haber una disminución de la señalización glutamatérgica a nivel de los receptores NMDA, pero los agonistas directos de estos receptores no tienen utilidad clínica por ser inespecíficos y sus muchos efectos indeseables. Dados los problemas de falta de eficacia o de efectos secundarios que presentan los fármacos que actúan directamentesobre los receptores ionotrópicos y mGlu2-3, se han ensayado otros que actúan por otros mecanismos, especialmente indirectos, como es la administración co-agonistas de los receptores NMDA (glicina o D-serina), inhibidores del transportador de la glicina (sarcosina, Bitopertin), AMPAkinas (CX-516) y agonistas de los receptores mGlu5. Sin embargo, a pesar de los constantes fracasos, el enfoque glutamatérgico en el tratamiento de la esquizofrenia no está agotado y es necesario revisar todos los aspectos teóricos que relacionan estos mecanismos neuroquímicos con la compleja sintomatología esta patología hasta que logremos moléculas que sean realmente eficaces y que tengan un perfil de efectos secundarios aceptable


It is accepted that both positive and negative symptoms of schizophrenia may be due to hypofunction of glutamatergic pathways leading to altered dopaminergic neurotransmission activity. Specifically, there may be diminished glutamatergic signaling at the level of the NMDA receptors, but direct receptor agonists have no clinical utility due to their nonspecific actions and undesirable side effects. Given the problems of ineffectiveness or side effects of drugs that act directly on ionotropic and metabotropicmGlu2-3 receptors, clinical trials have been conducted with other drugs that have other mechanisms of action, especially indirect mechanisms, such as the co-administration of NMDA agonists (glycine or D-serine), glycine transporter inhibitors (sarcosine bitopertin), ampakines (CX-516), andmGlu5 receptor agonists. However, despite repeated failures, the glutamatergic approach to the treatment of schizophrenia has not been exhausted and all theoretical aspects that relate these complex neurochemical mechanisms with symptoms of schizophrenia should be reviewed until we find truly effective molecules with an acceptable side effect profile


Assuntos
Humanos , Masculino , Feminino , Ácido Glutâmico/uso terapêutico , Esquizofrenia/tratamento farmacológico , Receptores de Neurotransmissores/metabolismo , Neurotransmissores/metabolismo , Neurotransmissores/farmacocinética , N-Metilaspartato/uso terapêutico , Receptores de N-Metil-D-Aspartato/uso terapêutico , Glicina/uso terapêutico , Sarcosina/uso terapêutico , Neuroquímica/métodos , Neuroquímica/tendências
13.
ChemMedChem ; 9(11): 2486-96, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25147058

RESUMO

The orexin system consists of two G-protein-coupled receptors, the orexin 1 and orexin 2 receptors, widely expressed in diverse regions of the brain, and two peptide agonists, orexin A and orexin B, which are produced in a small assembly of neurons in the lateral hypothalamus. The orexin system plays an important role in the maintenance of wakefulness. Several compounds (almorexant, SB-649868, suvorexant) have been in advanced clinical trials for treating primary insomnia. ACT-462206 is a new, potent, and selective dual orexin receptor antagonist (DORA) that inhibits the stimulating effects of the orexin peptides at both the orexin 1 and 2 receptors. It decreases wakefulness and increases non-rapid eye movement (non-REM) and REM sleep while maintaining natural sleep architectures in rat and dog electroencephalography/electromyography (EEG/EMG) experiments. ACT-462206 shows anxiolytic-like properties in rats without affecting cognition and motor function. It is therefore a potential candidate for the treatment of insomnia.


Assuntos
Encéfalo/metabolismo , Neurotransmissores/química , Antagonistas dos Receptores de Orexina , Pirrolidinas/química , Sulfonamidas/química , Animais , Barreira Hematoencefálica/metabolismo , Cães , Meia-Vida , Humanos , Células Madin Darby de Rim Canino , Masculino , Neurotransmissores/farmacocinética , Receptores de Orexina/metabolismo , Prolina/química , Pirrolidinas/farmacocinética , Ratos , Ratos Wistar , Estereoisomerismo , Relação Estrutura-Atividade , Sulfonamidas/farmacocinética
14.
Neuropharmacology ; 86: 259-72, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25107588

RESUMO

The NK3 receptor is a GPCR that is prominently expressed in limbic areas of the brain, many of which have been implicated in schizophrenia. Phase II clinical trials in schizophrenia with two selective NK3 antagonists (osanetant and talnetant) have demonstrated significant improvement in positive symptoms. The objective of this study was to characterize the properties of a novel dual NK2/NK3 antagonist, RO5328673. [(3)H]RO5328673 bound to a single saturable site on hNK2, hNK3 and gpNK3 with high-affinity. RO5328673 acted as an insurmountable antagonist at both human and guinea-pig NK3 receptors in the [(3)H]IP accumulation assay. In binding kinetic analyses, [(3)H]RO5328673 had fast association and dissociation rates at hNK2 while it had a fast association rate and a remarkably slow dissociation rate at gp and hNK3. In electrophysiological recordings of gp SNpc, RO5328673 inhibited the senktide-induced potentiation of spontaneous activity of dopaminergic neurons with an insurmountable mechanism of action. RO5328673 exhibited in-vivo activity in gerbils, robustly reversing the senktide-induced locomotor activity. The TM2 residue gpNK3-A114(2.58) (threonine in all other species) was identified as the critical residue for the RO5328673's slower dissociation kinetics and stronger insurmountable mode of antagonism in the guinea-pig as compared to hNK3-T139(2.58). Using site-directed mutagenesis, [(3)H]RO5328673 binding and rhodopsin-based modeling, the important molecular determinants of the RO5328673-binding pocket of hNK3 were determined. A comparison of the RO5328673-binding pocket with that of osanetant showed that two antagonists have similar contact sides on hNK3 binding crevice except for three mutations V95L(1.42), Y247W(5.38), V255I(5.46), which behaved differently between interacting modes of two antagonists in hNK3.


Assuntos
Carbamatos/farmacologia , Neurotransmissores/farmacologia , Piperidinas/farmacologia , Receptores da Neurocinina-3/antagonistas & inibidores , Sequência de Aminoácidos , Animais , Antipsicóticos/farmacologia , Sítios de Ligação , Carbamatos/farmacocinética , Fármacos do Sistema Nervoso Central/farmacologia , Neurônios Dopaminérgicos/efeitos dos fármacos , Neurônios Dopaminérgicos/fisiologia , Feminino , Gerbillinae , Cobaias , Células HEK293 , Humanos , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Masculino , Modelos Moleculares , Dados de Sequência Molecular , Mutação , Neurotransmissores/farmacocinética , Parte Compacta da Substância Negra/efeitos dos fármacos , Parte Compacta da Substância Negra/fisiologia , Fragmentos de Peptídeos/farmacologia , Piperidinas/farmacocinética , Receptores da Neurocinina-2/antagonistas & inibidores , Receptores da Neurocinina-2/metabolismo , Receptores da Neurocinina-3/agonistas , Receptores da Neurocinina-3/genética , Receptores da Neurocinina-3/metabolismo , Substância P/análogos & derivados , Substância P/farmacologia , Técnicas de Cultura de Tecidos
15.
Yao Xue Xue Bao ; 49(4): 450-6, 2014 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-24974460

RESUMO

Glioma is the most common form of brain cancer. Despite recent advances in the treatment of solid tumors, there are few effective treatments for malignant gliomas due to its infiltrative nature. It has important significance to improve the treatment of glioma through in-depth understanding the intracerebral metabolic characteristics and pharmacokinetics of chemotherapeutics. Brain microdialysis (B-MD), an effective method to monitor central nervous system anticancer drug disposition, conditions of drugs through the blood-brain barrier, basic pathophysiologic metabolism, bioactive compounds and the changes of neurotransmitter in brain, provides the unique opportunity to allow the simultaneous determination of unbound concentrations of drugs in several tissues, and directly measure gliomas biochemistry continuously. B-MD has been able to monitor the change of brain drugs, metabolites and neurotransmitters, dynamic analysis of the drug concentration and pharmacological effect after administration, pharmacodynamic interaction between drugs, receptor mechanism of drug transport, as well as feedback information of internal environment. B-MD is expected to provide reference for clinical individual chemotherapy of glioma, but also provide powerful tools for the evaluation of new anticancer drugs in vivo. In this review, a comprehensive overview of B-MD for studies on glioma is elucidated with special emphasis on its application to neurochemistry and pharmacokinetic studies.


Assuntos
Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Metabolômica/métodos , Microdiálise/métodos , Neurotransmissores/farmacocinética , Preparações Farmacêuticas/metabolismo , Animais , Antineoplásicos/farmacocinética , Barreira Hematoencefálica , Humanos , Espectroscopia de Ressonância Magnética , Tomografia por Emissão de Pósitrons
16.
Eksp Klin Farmakol ; 77(5): 38-44, 2014.
Artigo em Russo | MEDLINE | ID: mdl-25033571

RESUMO

Literature data concerning modern notions about the role of taurine in the central nervous system are analyzed. Mechanisms of the neuroprotective activity of taurine are described. Evidence showing the effects of taurine as neurotransmitter, neuromodulator, antioxidant, etc. is provided.


Assuntos
Antioxidantes/farmacocinética , Sistema Nervoso Central/metabolismo , Neurotransmissores/farmacocinética , Taurina/farmacocinética , Animais , Humanos
17.
Cold Spring Harb Protoc ; 2014(6): 584-90, 2014 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-24890218

RESUMO

Nitroaromatic photochemical protecting groups were developed for organic synthesis in 1966. Since the early 1990s, this type of chromophore has been used by neuroscientists to liberate a wide variety of amino acid neurotransmitters such as ACh, glutamate, GABA, and glycine, among others. Since 2001, several laboratories have used two-photon excitation of nitroaromatic cages for highly localized uncaging of glutamate in acute brain slices.


Assuntos
Sistemas de Liberação de Medicamentos , Neurotransmissores/farmacocinética , Nitrofenóis/metabolismo , Luz
18.
An. R. Acad. Farm ; 80(2): 347-361, abr.-jun. 2014. ilus, graf, tab
Artigo em Inglês | IBECS | ID: ibc-125902

RESUMO

Hormones are expressed during development in unexpected locations and stages, and this fact relates to their distinct functional roles in the embryo. In recent work, we found that the expression of Tyrosine Hydroxylase (TH, first enzyme of the catecholamine synthetic pathway) and the presence of catecholamines, antecede neural innervation in some tissues. We focus this overview on the vertebrate developing heart. TH transcripts were present in early cardiogenesis, and adrenergic as well as dopaminergic receptors were found in the cardiac region of chick embryos. We found direct effects of dopamine on cardiac gene expression and we have advanced in revealing the function of catecholamines on cardiac patterning


Las hormonas están expresadas durante el desarrollo en etapas y localizaciones inesperadas y este hecho se relaciona con sus distintas funciones en el embrión. Recientemente, hemos encontrado que la expresión de la Tirosina Hidroxilasa (TH, el primer enzima de la ruta de síntesis de catecolaminas) y la presencia de catecolaminas, anteceden a la inervación neural en algunos tejidos. Este artículo está centrado en el desarrollo del corazón de vertebrados. Los transcritos de TH se expresan durante la cardiogénesis temprana y se encontraron receptores dopaminérgicos y adrenérgicos en la región cardiaca del embrión de pollo. Hemos demostrado efectos directos de la dopamina sobre la expresión de genes cardiacos y hemos avanzado en caracterizar una función de las catecolaminas sobre la formación del patrón del corazón


Assuntos
Animais , Catecolaminas/farmacocinética , Coração/crescimento & desenvolvimento , Dopamina/farmacocinética , Tirosina 3-Mono-Oxigenase/análise , Vertebrados/crescimento & desenvolvimento , Hormônios/farmacocinética , Neurotransmissores/farmacocinética , Elementos Reguladores de Transcrição
19.
Expert Opin Drug Metab Toxicol ; 10(5): 759-66, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24684240

RESUMO

INTRODUCTION: Major depressive disorder (MDD), one of the most common disorders in medical practice and one of the leading causes of disability worldwide, is frequently comorbid with anxiety disorders. Vortioxetine (Lu AA21004) is a new antidepressant that combines a number of neurotransmitter reuptake and receptor effects that have been thought to predict efficacy as a treatment for depressive and anxiety disorders. AREAS COVERED: This review summarizes the pharmacology and neurobiology of vortioxetine. Studies of its efficacy and tolerability in major depression and generalized anxiety disorder are critically reviewed. EXPERT OPINION: Despite the fact that industry-sponsored studies are more likely than other clinical trials to support efficacy of the experimental drug, results have been mixed. Some studies supported that vortioxetine is superior to placebo in the treatment of MDD and some do not. Two studies supported the efficacy of vortioxetine in the treatment of generalized anxiety disorder and two do not. The incidence of sexual dysfunction has varied considerably in different studies, but cardiac effects and psychomotor impairment seem to be minimal. Advantages of vortioxetine over existing antidepressants are not yet clear.


Assuntos
Antidepressivos/farmacocinética , Transtorno Depressivo Maior/tratamento farmacológico , Piperazinas/farmacocinética , Sulfetos/farmacocinética , Ansiolíticos/efeitos adversos , Ansiolíticos/farmacocinética , Ansiolíticos/uso terapêutico , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Transtornos de Ansiedade/tratamento farmacológico , Transtornos de Ansiedade/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtorno Depressivo Maior/metabolismo , Resistência a Medicamentos , Humanos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neurotransmissores/efeitos adversos , Neurotransmissores/farmacocinética , Neurotransmissores/uso terapêutico , Piperazinas/efeitos adversos , Piperazinas/uso terapêutico , Sulfetos/efeitos adversos , Sulfetos/uso terapêutico , Vortioxetina
20.
Psychopharmacology (Berl) ; 231(17): 3517-24, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-24682501

RESUMO

RATIONALE: In order to improve upon the pharmacological properties of the neuroactive steroid ganaxolone, it was used as the starting point in the design of novel neurosteroids that replace the 17ß-acetyl side chain with an isoxazole bioisostere. OBJECTIVES: UCI-50027 (3-[3α-hydroxy-3ß-methyl-5α-androstan-17ß-yl]-5-(hydroxymethyl)isoxazole) was designed as an orally active neuroactive steroid specifically targeted at the gamma-aminobutyric acid(A) receptor (GABAAR). METHODS: UCI-50027 was tested in vitro in Xenopus oocytes expressing human GABAARs and in vivo as an anticonvulsant, for ataxic effects and for anxiolytic activity. RESULTS: In vitro, UCI-50027 dose-dependently enhanced the activity of GABA at human α1ß2γ2L, α2ß1γ2L, and α4ß3δ GABAARs. Consistent with its action as a positive allosteric modulator (PAM), it had no direct activity in the absence of GABA. UCI-50027 protected against acute pentylenetetrazol (PTZ)-induced convulsions with an ED50 of 6 mg/kg p.o. In the rotarod (RR) paradigm in mice, the AD50 (the ataxic dose where half of the animals fail the RR test) was found to be 38 mg/kg p.o., giving a therapeutic index (TI = RR AD50/PTZ ED50)∼6 versus 2.8 for ganaxolone. In the mouse-elevated plus maze (EPM) model for anxiety, UCI-50027 showed a minimum effective dose (MED) ≤0.3 mg/kg p.o. Thus, the TI (TI = RR AD50/EPM MED) for the compound as an anxiolytic is ≥127 versus 3.3 for ganaxolone. CONCLUSIONS: UCI-50027 is an orally active neuroactive steroid with pharmacological activity consistent with a GABAAR PAM that has an improved separation between anticonvulsant/anxiolytic and rotarod effects, potent activity as an anticonvulsant and anxiolytic when compared to ganaxolone.


Assuntos
Androstanos/farmacologia , Neurotransmissores/farmacologia , Animais , Ansiolíticos/farmacologia , Anticonvulsivantes/farmacologia , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Neurotransmissores/farmacocinética , Técnicas de Patch-Clamp , Pentilenotetrazol/antagonistas & inibidores , Equilíbrio Postural/efeitos dos fármacos , Pregnanolona/análogos & derivados , Pregnanolona/farmacocinética , Pregnanolona/farmacologia , Ratos , Ratos Sprague-Dawley , Receptores de GABA-A/efeitos dos fármacos , Xenopus
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