RESUMEN

The hiccup (Latin singultus) is an involuntary periodic contraction of the diaphragm followed by glottic closure, which can be a rare side effect of aripiprazole. In contrast to the structurally closely related aripiprazole, brexpiprazole was not associated with this particular adverse drug reaction. Having two very similar drugs that differ in their ability to induce hiccups represents a unique opportunity to gain insight into the receptors involved in the pathophysiology of the symptom and differences in clinical effects between aripiprazole and brexpiprazole. The overlap between maneuvers used to terminate paroxysmal supraventricular tachycardia and those employed to terminate bouts of hiccups suggests that activation of efferent vagal fibers can be therapeutic in both instances. Recent work seems to support a pivotal role for serotonin receptors in such vagal activation. It is unlikely that a unique receptor-drug interaction could explain the different effects of the examined drugs on hiccup. The different effect is most likely the consequence of several smaller effects at more than one receptor. Brexpiprazole is a highly affine (potent) α2C antagonist and, therefore, also an indirect 5-HT1A agonist. In contrast, aripiprazole is a partial 5-HT1A agonist (weak antagonist) and an HT3 antagonist. Activation of 5-HT1A receptors enhances vagal activity while HT3 blockade reduces it. Vagus nerve activation is therapeutic for hiccups. A definitive answer continues to be elusive.

Asunto(s)

Aripiprazol/farmacología , Hipo/inducido químicamente , Neurotransmisores/farmacología , Quinolonas/farmacología , Tiofenos/farmacología , Aripiprazol/efectos adversos , Aripiprazol/farmacocinética , Humanos , Neurotransmisores/efectos adversos , Neurotransmisores/farmacocinética , Quinolonas/efectos adversos , Quinolonas/farmacocinética , Tiofenos/efectos adversos , Tiofenos/farmacocinética

RESUMEN

OBJECTIVE: The aim of this study was to develop 99mTc-[HYNIC-X-D-Phe13]-BBN(7-14)NH2 derivatives using two different tripeptidic spacer groups (X=GGG and X=SSS) in order to improve its pharmacokinetics, in vitro stability, specific binding, and affinity. BACKGROUND: Bombesin (BBN), a 14-aminoacid amphibian peptide homolog of mammalian gastrinreleasing peptide (GRP), has demonstrated the ability to bind with high affinity and specificity to GRP receptor, which is overexpressed on a variety of human cancers. METHODS: Peptide conjugates labeled with 99mTc using tricine-EDDA and radiochemical purity was assessed by TLC and HPLC. The stability of radio conjugates was evaluated in the presence of saline and human serum. Affinity, internalization, and also dissociation Constant was evaluated using MDAMB- 231 and PC-3 cell line. Biodistribution study was performed in BALB/C mice. RESULTS: Labeling yield of ˃95% was obtained. The change introduced in the BBN sequence increased plasma stability. In vitro blocking studies showed that binding and internalization of both radiolabeled peptides are mediated by their receptors on the surface of MDA-MB-231 and PC-3 cells. Biodistribution results demonstrated a rapid blood clearance, with predominantly renal excretion. Specific binding in GRP receptor-positive tissues, such as pancreas was confirmed with a blocking study. CONCLUSION: The introduction of the spacer sequence between chelator and BBN(7-14) led to improved bidistribution. Analog with tri-Gly spacer is the more promising radiopeptide for targeting GRP receptors than Ser conjugates. Therefore, these analogs can be considered as a candidate for the identification of bombesin-positive tumors.

Asunto(s)

Bombesina/farmacocinética , Neurotransmisores/farmacocinética , Radiofármacos/farmacocinética , Animales , Línea Celular Tumoral , Cromatografía Líquida de Alta Presión , Cromatografía en Capa Delgada , Modelos Animales de Enfermedad , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Células PC-3 , Radioquímica , Distribución Tisular

RESUMEN

Gastrin-releasing peptide receptors (GRPRs) are promising targets in oligometastatic prostate cancer. We have recently used 55Co (T1/2 = 17.5 h) as a label for next day PET imaging of GRPR expression obtaining high imaging contrast. The radionuclide-chelator combination can significantly influence the biodistribution of radiopeptides. Therefore, in this study, we hypothesized that the properties of 55Co-labeled PEG2-RM26 can be improved by identifying the optimal macrocyclic chelator. All analogues (X-PEG2-RM26, X = NOTA,NODAGA,DOTA,DOTAGA) were successfully labeled with radiocobalt with high yields and demonstrated high stability. The radiopeptides bound specifically and with picomolar affinity to GRPR and their cellular processing was characterized by low internalization. The best binding capacity was found for DOTA-PEG2-RM26. Ex vivo biodistribution in PC-3 xenografted mice was characterized by rapid blood clearance via renal excretion. Tumor uptake was similar for all conjugates at 3 h pi, exceeding the uptake in all other organs. Higher kidney uptake and longer retention were associated with N-terminal negative charge (DOTAGA-containing conjugate). Tumor-to-organ ratios increased over time for all constructs, although significant chelator-dependent differences were observed. Concordant with affinity measurements, DOTA-analog had the best retention of activity in tumors, resulting in the highest tumor-to-blood ratio 24 h pi, which translated into high contrast PET/CT imaging (using 55Co).

Asunto(s)

Bombesina/farmacocinética , Radioisótopos de Cobalto/farmacocinética , Compuestos Macrocíclicos/química , Compuestos Organometálicos/química , Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/patología , Receptores de Bombesina/antagonistas & inhibidores , Animales , Apoptosis , Bombesina/análogos & derivados , Bombesina/farmacología , Proliferación Celular , Quelantes/química , Femenino , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos NOD , Ratones Desnudos , Ratones SCID , Neurotransmisores/química , Neurotransmisores/farmacocinética , Neurotransmisores/farmacología , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto

Asunto(s)

Biotransformación/genética , Catecol O-Metiltransferasa , Neurotransmisores/farmacocinética , Variantes Farmacogenómicas/genética , Transmisión Sináptica/genética , Biomarcadores Farmacológicos/análisis , Catecol O-Metiltransferasa/genética , Catecol O-Metiltransferasa/metabolismo , Pruebas Genéticas/métodos , Humanos , Farmacogenética , Polimorfismo de Nucleótido Simple , Utilización de Procedimientos y Técnicas

RESUMEN

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.

Asunto(s)

Antipsicóticos/farmacología , Neurotransmisores/farmacología , Receptores de GABA-B/metabolismo , Receptores Muscarínicos/metabolismo , Esquizofrenia/tratamiento farmacológico , Regulación Alostérica , Animales , Antipsicóticos/farmacocinética , Benzamidas/farmacocinética , Benzamidas/farmacología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Ciclopentanos/farmacocinética , Ciclopentanos/farmacología , Modelos Animales de Enfermedad , Quimioterapia Combinada , Potenciales Postsinápticos Excitadores/efectos de los fármacos , Potenciales Postsinápticos Excitadores/fisiología , Indoles/farmacocinética , Indoles/farmacología , Masculino , Ratones , Neurotransmisores/farmacocinética , Piridinas/farmacocinética , Piridinas/farmacología , Pirimidinas/farmacocinética , Pirimidinas/farmacología , Esquizofrenia/metabolismo , Tiofenos/farmacocinética , Tiofenos/farmacología

RESUMEN

: 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.

Asunto(s)

Trastornos Relacionados con Alcohol/tratamiento farmacológico , Conducta Adictiva/tratamiento farmacológico , Trastornos Relacionados con Cocaína/tratamiento farmacológico , Neurotransmisores/farmacología , Fumar/tratamiento farmacológico , Topiramato/farmacología , Humanos , Neurotransmisores/efectos adversos , Neurotransmisores/farmacocinética , Topiramato/efectos adversos , Topiramato/farmacocinética

RESUMEN

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.

Asunto(s)

Amígdala del Cerebelo/metabolismo , Columbidae/anatomía & histología , Receptores de Neurotransmisores/metabolismo , Amígdala del Cerebelo/efectos de los fármacos , Animales , Autorradiografía , Columbidae/metabolismo , Neurotransmisores/farmacocinética , Unión Proteica/efectos de los fármacos , Unión Proteica/fisiología , Tritio/farmacocinética

RESUMEN

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.

Asunto(s)

Amígdala del Cerebelo/metabolismo , Mapeo Encefálico , Vías Nerviosas/metabolismo , Receptores de Neurotransmisores/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Amígdala del Cerebelo/diagnóstico por imagen , Amígdala del Cerebelo/efectos de los fármacos , Autopsia , Autorradiografía , Femenino , Lateralidad Funcional , Humanos , Procesamiento de Imagen Asistido por Computador , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Vías Nerviosas/diagnóstico por imagen , Neurotransmisores/farmacocinética , Tritio/farmacocinética

RESUMEN

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.

Asunto(s)

Neurotransmisores/efectos adversos , Neurotransmisores/farmacocinética , Canales Catiónicos TRPV/antagonistas & inhibidores , Administración Oral , Adulto , Área Bajo la Curva , Temperatura Corporal/efectos de los fármacos , Capsaicina/farmacología , Estudios Cruzados , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Ayuno , Femenino , Humanos , Masculino , Umbral del Dolor/efectos de los fármacos , Datos Preliminares

RESUMEN

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.

Asunto(s)

Ingestión de Alimentos/efectos de los fármacos , Ghrelina , Leptina/metabolismo , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa , Receptores del Polipéptido Activador de la Adenilato-Ciclasa Hipofisaria/metabolismo , Animales , Apetito/efectos de los fármacos , Regulación del Apetito/fisiología , Relación Dosis-Respuesta a Droga , Conducta Alimentaria , Tracto Gastrointestinal/metabolismo , Ghrelina/antagonistas & inhibidores , Ghrelina/sangre , Péptido 1 Similar al Glucagón/sangre , Inyecciones Intraperitoneales , Masculino , Ratones , Modelos Animales , Neurotransmisores/administración & dosificación , Neurotransmisores/farmacocinética , Péptido YY/sangre , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/administración & dosificación , Polipéptido Hipofisario Activador de la Adenilato-Ciclasa/farmacocinética

RESUMEN

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.

Asunto(s)

Bloqueadores de los Canales de Calcio/química , Cinarizina/química , Neurotransmisores/química , Animales , Bloqueadores de los Canales de Calcio/farmacocinética , Bloqueadores de los Canales de Calcio/farmacología , Química Farmacéutica , Cinarizina/farmacocinética , Cinarizina/farmacología , Antagonistas de Dopamina/química , Estabilidad de Medicamentos , Antagonistas de los Receptores Histamínicos H1/química , Humanos , Estructura Molecular , Neurotransmisores/farmacocinética , Neurotransmisores/farmacología , Antagonistas de la Serotonina/química , Tecnología Farmacéutica/métodos

RESUMEN

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.

Asunto(s)

Neurotransmisores/química , Neurotransmisores/farmacología , Pregnanolona/análogos & derivados , Pregnanolona/farmacología , Receptores de GABA/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Humanos , Ratones , Neurotransmisores/farmacocinética , Pregnanolona/farmacocinética , Ratas , Relación Estructura-Actividad

RESUMEN

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.

Asunto(s)

Antidepresivos/farmacología , Medicamentos Herbarios Chinos/farmacología , Inhibidores de la Captación de Neurotransmisores/farmacología , Sinaptosomas/efectos de los fármacos , Animales , Citalopram/farmacocinética , Cuerpo Estriado/citología , Depresión/tratamiento farmacológico , Modelos Animales de Enfermedad , Preferencias Alimentarias/efectos de los fármacos , Lóbulo Frontal/citología , Humanos , Masculino , Ratones , Ratones Endogámicos ICR , Neurotransmisores/farmacocinética , Proteínas de Transporte de Neurotransmisores en la Membrana Plasmática/metabolismo , Unión Proteica/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Saponinas/farmacología , Saponinas/uso terapéutico , Sacarosa/administración & dosificación , Tritio/farmacocinética

RESUMEN

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.

Asunto(s)

Mapeo Encefálico , Receptores de Neurotransmisores/metabolismo , Lóbulo Temporal/anatomía & histología , Lóbulo Temporal/metabolismo , Anciano , Autorradiografía , Análisis por Conglomerados , Procesamiento Automatizado de Datos , Cara , Femenino , Humanos , Masculino , Neurotransmisores/farmacocinética , Cambios Post Mortem , Lóbulo Temporal/efectos de los fármacos , Tritio/farmacocinética

RESUMEN

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

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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

Asunto(s)

Humanos , Masculino , Femenino , Ácido Glutámico/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Receptores de Neurotransmisores/metabolismo , Neurotransmisores/metabolismo , Neurotransmisores/farmacocinética , N-Metilaspartato/uso terapéutico , Receptores de N-Metil-D-Aspartato/uso terapéutico , Glicina/uso terapéutico , Sarcosina/uso terapéutico , Neuroquímica/métodos , Neuroquímica/tendencias

RESUMEN

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.

Asunto(s)

Carbamatos/farmacología , Neurotransmisores/farmacología , Piperidinas/farmacología , Receptores de Neuroquinina-3/antagonistas & inhibidores , Secuencia de Aminoácidos , Animales , Antipsicóticos/farmacología , Sitios de Unión , Carbamatos/farmacocinética , Fármacos del Sistema Nervioso Central/farmacología , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/fisiología , Femenino , Gerbillinae , Cobayas , Células HEK293 , Humanos , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Modelos Moleculares , Datos de Secuencia Molecular , Mutación , Neurotransmisores/farmacocinética , Porción Compacta de la Sustancia Negra/efectos de los fármacos , Porción Compacta de la Sustancia Negra/fisiología , Fragmentos de Péptidos/farmacología , Piperidinas/farmacocinética , Receptores de Neuroquinina-2/antagonistas & inhibidores , Receptores de Neuroquinina-2/metabolismo , Receptores de Neuroquinina-3/agonistas , Receptores de Neuroquinina-3/genética , Receptores de Neuroquinina-3/metabolismo , Sustancia P/análogos & derivados , Sustancia P/farmacología , Técnicas de Cultivo de Tejidos

RESUMEN

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.

Asunto(s)

Encéfalo/metabolismo , Neurotransmisores/química , Antagonistas de los Receptores de Orexina , Pirrolidinas/química , Sulfonamidas/química , Animales , Barrera Hematoencefálica/metabolismo , Perros , Semivida , Humanos , Células de Riñón Canino Madin Darby , Masculino , Neurotransmisores/farmacocinética , Receptores de Orexina/metabolismo , Prolina/química , Pirrolidinas/farmacocinética , Ratas , Ratas Wistar , Estereoisomerismo , Relación Estructura-Actividad , Sulfonamidas/farmacocinética

RESUMEN

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.

Asunto(s)

Neoplasias Encefálicas/metabolismo , Glioma/metabolismo , Metabolómica/métodos , Microdiálisis/métodos , Neurotransmisores/farmacocinética , Preparaciones Farmacéuticas/metabolismo , Animales , Antineoplásicos/farmacocinética , Barrera Hematoencefálica , Humanos , Espectroscopía de Resonancia Magnética , Tomografía de Emisión de Positrones

RESUMEN

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.

Asunto(s)

Antioxidantes/farmacocinética , Sistema Nervioso Central/metabolismo , Neurotransmisores/farmacocinética , Taurina/farmacocinética , Animales , Humanos

RESUMEN

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.

Asunto(s)

Sistemas de Liberación de Medicamentos , Neurotransmisores/farmacocinética , Nitrofenoles/metabolismo , Luz