RESUMEN
3-Aryl-indole and 3-aryl-indazole derivatives were identified as potent and selective Nav1.7 inhibitors. Compound 29 was shown to be efficacious in the mouse formalin assay and also reduced complete Freund's adjuvant (CFA)-induced thermal hyperalgesia and chronic constriction injury (CCI) induced cold allodynia and models of inflammatory and neuropathic pain, respectively, following intraperitoneal (IP) doses of 30 mg/kg. The observed efficacy could be correlated with the mouse dorsal root ganglion exposure and NaV1.7 potency associated with 29.
Asunto(s)
Indazoles/química , Indoles/química , Canal de Sodio Activado por Voltaje NAV1.7/química , Neuralgia/tratamiento farmacológico , Sulfonamidas/química , Bloqueadores del Canal de Sodio Activado por Voltaje/uso terapéutico , Animales , Evaluación Preclínica de Medicamentos , Células HEK293 , Semivida , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Masculino , Ratones , Canal de Sodio Activado por Voltaje NAV1.7/metabolismo , Neuralgia/patología , Técnicas de Placa-Clamp , Relación Estructura-Actividad , Sulfonamidas/metabolismo , Sulfonamidas/uso terapéutico , Bloqueadores del Canal de Sodio Activado por Voltaje/química , Bloqueadores del Canal de Sodio Activado por Voltaje/metabolismoRESUMEN
Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-d-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32, a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses.
Asunto(s)
Oxazolidinonas/farmacología , Piridinas/farmacología , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Humanos , Ratones , Estructura Molecular , Oxazolidinonas/síntesis química , Oxazolidinonas/química , Piridinas/síntesis química , Piridinas/química , Ratas , Relación Estructura-ActividadRESUMEN
Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.
Asunto(s)
Convulsivantes/química , Oxazolidinonas/química , Receptor del Glutamato Metabotropico 5/metabolismo , Regulación Alostérica/efectos de los fármacos , Animales , Convulsivantes/metabolismo , Convulsivantes/farmacología , Humanos , Ratones , Ratones Endogámicos C57BL , Oxazolidinonas/metabolismo , Oxazolidinonas/farmacología , Ratas , Receptor del Glutamato Metabotropico 5/agonistas , Receptor del Glutamato Metabotropico 5/química , Reconocimiento en Psicología/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.
RESUMEN
Schizophrenia patients exhibit dysfunctional gamma oscillations in response to simple auditory stimuli or more complex cognitive tasks, a phenomenon explained by reduced NMDA transmission within inhibitory/excitatory cortical networks. Indeed, a simple steady-state auditory click stimulation paradigm at gamma frequency (~40 Hz) has been reproducibly shown to reduce entrainment as measured by electroencephalography (EEG) in patients. However, some investigators have reported increased phase locking factor (PLF) and power in response to 40 Hz auditory stimulus in patients. Interestingly, preclinical literature also reflects this contradiction. We investigated whether a graded deficiency in NMDA transmission can account for such disparate findings by administering subanesthetic ketamine (1-30 mg/kg, i.v.) or vehicle to conscious rats (n=12) and testing their EEG entrainment to 40 Hz click stimuli at various time points (~7-62 min after treatment). In separate cohorts, we examined in vivo NMDA channel occupancy and tissue exposure to contextualize ketamine effects. We report a robust inverse relationship between PLF and NMDA occupancy 7 min after dosing. Moreover, ketamine could produce inhibition or disinhibition of the 40 Hz response in a temporally dynamic manner. These results provide for the first time empirical data to understand how cortical NMDA transmission deficit may lead to opposite modulation of the auditory steady-state response (ASSR). Importantly, our findings posit that 40 Hz ASSR is a pharmacodynamic biomarker for cortical NMDA function that is also robustly translatable. Besides schizophrenia, such a functional biomarker may be of value to neuropsychiatric disorders like bipolar and autism spectrum where 40 Hz ASSR deficits have been documented.
Asunto(s)
Corteza Cerebral/fisiología , Potenciales Evocados Auditivos , Ritmo Gamma , Receptores de N-Metil-D-Aspartato/fisiología , Estimulación Acústica , Animales , Biomarcadores , Corteza Cerebral/efectos de los fármacos , Maleato de Dizocilpina/farmacocinética , Electroencefalografía , Antagonistas de Aminoácidos Excitadores/administración & dosificación , Ketamina/administración & dosificación , Masculino , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Procesamiento de Señales Asistido por ComputadorRESUMEN
The cerebellum plays a major role in not only modulating motor activity, but also contributing to other functions, including nociception. The intermediate hemisphere of the cerebellum receives sensory input from the limbs. With the extensive connection between the cerebellum to brain-stem structures and cerebral cortex, it is possible that the cerebellum may facilitate the descending system to modulate spinal dorsal horn activity. This study provided the first evidence to support this hypothesis. Thirty-one wide-dynamic-range neurons from the left lumbar and 27 from the right lumbar spinal dorsal horn were recorded in response to graded mechanical stimulation (brush, pressure, and pinch) at the hind paws. Electrical stimulation of the cerebellar cortex of the left intermediate hemisphere significantly reduced spinal cord dorsal horn neuron-evoked responses bilaterally in response to peripheral high-intensity mechanical stimuli. It is concluded that the cerebellum may play a potential antinociceptive role, probably through activating descending inhibitory pathways indirectly.
Asunto(s)
Vías Aferentes/fisiología , Corteza Cerebelosa/fisiología , Inhibición Neural/fisiología , Nocicepción/fisiología , Células del Asta Posterior/fisiología , Vías Aferentes/citología , Animales , Corteza Cerebelosa/citología , Estimulación Eléctrica , Masculino , Estimulación Física , Células del Asta Posterior/citología , Ratas , Ratas Sprague-DawleyRESUMEN
In this study, we investigated dynamic changes in light scattering and hemoglobin oxygen saturation (S(sc)O(2)) on the rat spinal cord due to peripheral electrical stimulation by measuring near infrared (NIR) and visible spectroscopy, respectively. The spectral slope in the wavelength region between 700 and 900 nm is used as an index (S(NIR)) to quantify light scattering. With a 100-mum (source-detector separation) fiber-optic needle probe, optical reflectance was measured from the left lumbar region, specifically LL5, of the spinal cord surface at a height of 575 mum from the spinal cord surface. Graded electrical stimulations from 20 to 50 V, in increments of 10 V, were given to the plantar surface of the rat left hind paw for a period of 20 s. Changes in both light scattering (S(NIR)) and S(sc)O(2) were determined as a difference between the baseline and the maximum of slope value and hemoglobin oxygen saturation, respectively, during the stimulation period. There were significant differences in both S(NIR) and S(sc)O(2) during stimulation, with the average percentage changes of 10.9% and 15.5%, respectively. We observed that both S(NIR) and S(sc)O(2) measured at the spinal cord are insensitive to the intensity of the electrical stimulus, which is possibly caused by the nonlinear process of neurovascular coupling. Our finding essentially indicates that peripheral electrical stimulation results in significant changes in both light scattering and hemoglobin oxygen saturation on the rat spinal cord, and ignoring light scattering changes could lead to possible negative offsets of hemodynamic parameters (oxy-, deoxy-, and total hemoglobin concentrations) obtained in the functional optical imaging in the brain.
Asunto(s)
Hemoglobinas/química , Oxígeno/sangre , Médula Espinal/química , Médula Espinal/metabolismo , Algoritmos , Animales , Interpretación Estadística de Datos , Estimulación Eléctrica , Luz , Oxihemoglobinas/química , Ratas , Ratas Sprague-Dawley , Dispersión de Radiación , Corteza Somatosensorial/metabolismo , Corteza Somatosensorial/fisiología , Espectroscopía Infrarroja CortaRESUMEN
UNLABELLED: Approximately 1 in 5 adults in the United States are affected by the pain, disability, and decreased quality of life associated with arthritis. The primary focus of treatment is on reducing joint inflammation and pain through a variety of pharmacotherapies, each of which is associated with various side effects. Hyperbaric oxygen therapy is an alternative treatment that has been recommended to treat a variety of inflammatory diseases, ranging from chronic brain injury to exercise induced muscle soreness. The purpose of this set of experiments was to explore the effect of hyperbaric oxygen therapy on joint inflammation and mechanical hyperalgesia in an animal model of arthritis, and compare these effects to treatment with aspirin. Hyperbaric oxygen therapy significantly reduced both joint inflammation and hyperalgesia. As compared with aspirin treatment, hyperbaric treatment was equally as effective in decreasing joint inflammation and hyperalgesia. PERSPECTIVE: This article reports that hyperbaric oxygen treatment decreases pain and inflammation in an animal model of arthritis. The effect of hyperbaric oxygen treatment is very similar in magnitude to the effect of acetylsalicylic acid treatment. Potentially, hyperbaric oxygen could be used to treat pain and inflammation in patients with arthritis.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Artritis/terapia , Aspirina/uso terapéutico , Oxigenoterapia Hiperbárica/métodos , Animales , Artritis/inducido químicamente , Artritis/patología , Conducta Animal , Carragenina , Modelos Animales de Enfermedad , Edema/inducido químicamente , Edema/patología , Edema/terapia , Masculino , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The purpose of this study is to investigate the values of hemoglobin oxygen saturation in the sciatic nerve of the rat following spinal nerve ligation. An optical spectroscopic technique along with a fiber optic probe was used to test the hypothesis that demyelination and degeneration after nerve injury lead to a significant decrease in the percentage of hemoglobin oxygen saturation. A modified spinal nerve ligation method was used to induce the degeneration, and three types of ligation on left spinal nerve (L4, L4 and L5, L5) were performed in rats. The optical reflectance measurements were taken from the left and right sciatic nerves on postoperative days 1, 4, 7, and 14. No significant difference was found among the three types of ligation, nor was between left and right sciatic nerve at postoperative day 1. Significant decreases in oxygen saturation percentages were found between left and right sciatic nerves at postoperative days 4, 7, and 14. This study continues to show the effectiveness of optical methods in determining/differentiating tissue properties, providing an excellent and robust in vivo technique that can have a potential clinical application in detecting demyelination and degeneration of the nervous system.
Asunto(s)
Hemoglobinas/metabolismo , Consumo de Oxígeno/fisiología , Nervio Ciático/metabolismo , Algoritmos , Animales , Calibración , Interpretación Estadística de Datos , Ligadura , Masculino , Ratas , Ratas Sprague-Dawley , Espectroscopía Infrarroja Corta , Nervios Espinales/fisiologíaRESUMEN
Our goal is to quantify scattering properties of near-IR light in the rat spinal cord region and to differentiate healthy and demyelinated peripheral nerves intraoperatively based on differential light scattering. For the rat spinal cord, optical reflectance is measured from the spinal cord surface at spatial intervals of 1 mm using a needle probe. Data are acquired from left and right lumbar regions of the animals as well as on the central blood vessels. The reduced scattering coefficient mu(s)' is found to be higher (34.2+/-2.1 cm(-1)) in the lumbar regions of the spinal cord than on the central blood vessel (19.9+/-1.0 cm(-1)). This methodology is extended to detect differences in the rat sciatic nerves following left L4 spinal nerve ligation. The reflectance is taken at the same five regions at postoperative days 1, 4, 7, and 14. Significant differences are seen in both the spectral slope and mu(s)' values on postoperative days 4, 7, and 14, indicating that either of the two quantities could be used as a marker for demyelination. We prove the usefulness of the technique, which may have a possible clinical application for minimally invasive, intraoperative diagnosis and monitoring of demyelination diseases, such as multiple sclerosis in the central nervous system or degeneration of the peripheral nervous system.
Asunto(s)
Refractometría/métodos , Nervio Ciático/patología , Neuropatía Ciática/patología , Espectrofotometría Infrarroja/métodos , Médula Espinal/patología , Cirugía Asistida por Computador/métodos , Animales , Cuidados Intraoperatorios/métodos , Masculino , Ratas , Ratas Sprague-Dawley , Reproducibilidad de los Resultados , Dispersión de Radiación , Nervio Ciático/fisiopatología , Neuropatía Ciática/fisiopatología , Sensibilidad y Especificidad , Médula Espinal/fisiopatologíaRESUMEN
Cortical stimulation has been demonstrated to alleviate certain pain conditions. The aim of this study was to determine the responses of the spinal cord dorsal horn neurons to stimulation of the primary somatosensory cortex (SSC). We hypothesized that direct stimulation of the SSC will inhibit the activity of spinal dorsal horn neurons by activating the descending inhibitory system. Thirty-four wide dynamic range spinal dorsal horn neurons were recorded in response to graded mechanical stimulation (brush, pressure, and pinch) at their respective receptive fields while a stepwise electrical stimulation (300 Hz, 0.1 ms, at 10, 20, and 30 V) was applied in the SSC through a bipolar tungsten electrode. The responses to brush at control, 10 V, 20 V, 30 V, and recovery were 16.0 +/- 2.3, 15.8 +/- 2.2, 14.6 +/- 1.8, 14.8 +/- 2.0, and 17.0 +/- 2.2 spikes/s, respectively. The responses to pressure at control, 10 V, 20 V, 30 V, and recovery were 44.7 +/- 5.5, 37.0 +/- 5.6, 29.5 +/- 4.8, 31.6 +/- 5.2, and 43.2 +/- 5.7 spikes/s, respectively. The responses to pinch at control, 10 V, 20 V, 30 V, and recovery were 58.1 +/- 7.0, 42.9 +/- 5.5, 34.8 +/- 3.9, 34.6 +/- 4.4, and 52.6 +/- 6.0 spikes/s, respectively. Significant decreases of the dorsal horn neuronal responses to pressure and pinch were observed during SSC stimulation. It is concluded that electrical stimulation of the SSC produces transient inhibition of the responses of spinal cord dorsal horn neurons to higher intensity mechanical stimuli without affecting innocuous stimuli.
Asunto(s)
Potenciales de Acción/fisiología , Estimulación Eléctrica , Inhibición Neural/efectos de los fármacos , Células del Asta Posterior/fisiología , Corteza Somatosensorial/efectos de la radiación , Médula Espinal/citología , Análisis de Varianza , Animales , Relación Dosis-Respuesta en la Radiación , Lateralidad Funcional , Masculino , Inhibición Neural/fisiología , Estimulación Física/métodos , Células del Asta Posterior/efectos de la radiación , Ratas , Ratas Sprague-Dawley , Corteza Somatosensorial/fisiología , Estadística como AsuntoRESUMEN
Motor cortex stimulation (MCS) has been used clinically as a tool for the control for central post-stroke pain and neuropathic facial pain. The underlying mechanisms involved in the antinociceptive effect of MCS are not clearly understood. We hypothesize that the antinociceptive effect is through the modulation of the spinal dorsal horn neuron activity. Thirty-two wide dynamic range spinal dorsal horn neurons were recorded, in response to graded mechanical stimulation (brush, pressure, and pinch) at their respective receptive fields, while a stepwise electrical stimulation was applied simultaneously in the motor cortex. The responses to brush at control, 10 V, 20 V, and 30 V, and recovery were 11.5+/-1.6, 12.1+/-2.6, 11.1+/-2.2, 10.5+/-2.1, and 13.2+/-2.5 spikes/s, respectively. The responses to pressure at control, 10 V, 20 V, and 30 V, and recovery were 33.2+/-6.1, 22.9+/-5.3, 20.5+/-5.0, 17.3+/-3.8, and 27.0+/-4.0 spikes/s, respectively. The responses to pinch at control, 10 V, 20 V, and 30 V, and recovery were 37.2+/-6.4, 26.3+/-4.7, 25.9+/-4.7, 22.5+/-4.3, and 35.0+/-6.2 spikes/s, respectively. It is concluded that, in the rat, electrical stimulation of the motor cortex produces significant transient inhibition of the responses of spinal cord dorsal horn neurons to higher intensity mechanical stimuli without affecting their response to an innocuous stimulus.
Asunto(s)
Vías Eferentes/fisiología , Terapia por Estimulación Eléctrica , Corteza Motora/fisiología , Inhibición Neural/fisiología , Dolor/fisiopatología , Células del Asta Posterior/fisiología , Potenciales de Acción/fisiología , Vías Aferentes/fisiología , Animales , Tronco Encefálico/fisiología , Lateralidad Funcional/fisiología , Masculino , Mecanorreceptores/fisiología , Modelos Neurológicos , Nociceptores/fisiología , Manejo del Dolor , Estimulación Física , Ratas , Ratas Sprague-DawleyRESUMEN
The anterior cingulate cortex (ACC) is involved in the affective and motivational aspect of pain perception. Behavioral studies show a decreased avoidance behavior to noxious stimuli without change in mechanical threshold after stimulation of the ACC. However, as part of the neural circuitry of behavioral reflexes, there is no evidence showing that ACC stimulation alters dorsal horn neuronal responses. We hypothesize that ACC stimulation has two phases: a short-term phase in which stimulation elicits antinociception and a long-term phase that follows stimulation to change the affective response to noxious input. To begin testing this hypothesis, the purpose of this study was to examine the response of spinal cord dorsal horn neurons during stimulation of the ACC. Fifty-eight wide dynamic range spinal cord dorsal horn neurons from adult Sprague-Dawley rats were recorded in response to graded mechanical stimuli (brush, pressure, and pinch) at their respective receptive fields, while simultaneous stepwise electrical stimulations (300 Hz, 0.1 ms, at 10, 20, and 30 V) were applied in the ACC. The responses to brush at control, 10, 20, and 30 V, and recovery were 14.2 +/- 1.4, 12.3 +/- 1.2, 10.9 +/- 1.2, 10.3 +/- 1.1, and 14.1 +/- 1.4 spikes/s, respectively. The responses to pressure at control, 10, 20, and 30 V, and recovery were 39.8 +/- 4.7, 25.6 +/- 3.0, 25.0 +/- 3.0, 21.6 +/- 2.4, and 34.2 +/- 3.7 spikes/s, respectively. The responses to pinch at control, 10, 20, and 30 V, and recovery were 40.7 +/- 3.8, 30.6 +/- 3.1, 27.8 +/- 2.8, 27.2 +/- 3.2, and 37.4 +/- 3.9 spikes/s, respectively. We conclude that electrical stimulation of the ACC induces significant inhibition of the responses of spinal cord dorsal horn neurons to noxious mechanical stimuli. The stimulation-induced inhibition begins to recover as soon as the stimulation is terminated. These results suggest differential short-term and long-term modulatory effects of the ACC stimulation on nociceptive circuits.
Asunto(s)
Estimulación Eléctrica/métodos , Giro del Cíngulo/efectos de la radiación , Células del Asta Posterior/efectos de la radiación , Potenciales de Acción/fisiología , Potenciales de Acción/efectos de la radiación , Análisis de Varianza , Animales , Relación Dosis-Respuesta en la Radiación , Lateralidad Funcional/efectos de la radiación , Giro del Cíngulo/fisiología , Masculino , Modelos Neurológicos , Células del Asta Posterior/fisiología , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
We have recently developed an optical spectroscopy technique to monitor light scattering changes of the nervous system in vivo. Near infrared (NIR) spectroscopy emphasizes the detection of light scattering properties, which are prominent within the wavelength range of 700 to 850 nm wavelength. The purpose of this study is to test the hypothesis that demyelination and degeneration of the sciatic nerves after nerve injury will lead to a change in light scattering properties and be detected by the NIR technique. Left spinal nerve ligations (L4, L4 and L5, L5) were performed in rats. The scattering properties of the left (ligated) and right (control) sciatic nerve were measured by the NIR reflectance using a bifurcated needle probe at postoperative days 1, 4, 7, and 14. The results show that there was no significant difference among three types of ligation, and neither did the readings between left and right sciatic nerve at postoperative day 1. Significant decreases in light scattering indexes were found between left and right sciatic nerves at postoperative days 4, 7, and 14. It is concluded that our initial hypothesis is proven, suggesting that the NIR technique may have a potential for clinical application in detecting demyelination and degeneration of the nervous system.