RESUMEN
This meeting report highlights the main topics presented at the conference "Chronic Inflammatory and Neuropathic Pain," convened jointly by the New York Academy of Sciences, MedImmune, and Grünenthal GmbH, on June 2-3, 2011, with the goal of providing a conducive environment for lively, informed, and synergistic conversation among participants from academia, industry, clinical practice, and government to explore new frontiers in our understanding and treatment of chronic and neuropathic pain. The program included leading and emerging investigators studying the pathophysiological mechanisms underlying neuropathic and chronic pain, and experts in the clinical development of pain therapies. Discussion included novel issues, current challenges, and future directions of basic research in pain and preclinical and clinical development of new therapies for chronic pain.
Asunto(s)
Dolor Crónico , Inflamación/fisiopatología , Neuralgia , Manejo del Dolor/métodos , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Investigación Biomédica , Dolor Crónico/tratamiento farmacológico , Dolor Crónico/fisiopatología , Humanos , Neuralgia/tratamiento farmacológico , Neuralgia/fisiopatología , Investigación Biomédica TraslacionalRESUMEN
The objective of this study was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model of the static allodynia response to pregabalin with and without sildenafil in a chronic constriction injury model of neuropathic pain. Six treatment groups were evaluated every 30 min for 6 h. Rats were treated with either 1) a saline infusion; 2) a 2-h pregabalin infusion at 4 mgxkg(-1)xh(-1); 3) a 2-h pregabalin infusion at 10 mgxkg(-1)xh(-1); 4) a 2.2-mg loading dose + 12 mgxkg(-1)xmin(-1) infusion of sildenafil; 5) a 2-h pregabalin infusion at 1.6 mgxkg(-1)xh(-1) with sildenafil; and 6) a 2-h infusion of pregabalin at 4 mgxkg(-1)xh with sildenafil. The static allodynia endpoint was modeled by using three population PD approaches: 1) the behavior of the injured paw using a three-category ordinal logistic regression model; 2) paw withdrawal threshold (PWT) (g) between the injured and uninjured paw using the Hill equation with a baseline function; and 3) the baseline normalized difference in PWT between the injured and uninjured paw. The categorical model showed a significant shift in the concentration-response relationship of pregabalin to lower concentrations with concomitant sildenafil. Likewise, the continuous PK-PD models demonstrated a reduction in the EC(50) of pregabalin necessary for PD response in the presence of sildenafil. The difference-transformed PD model resulted in a 54.4% (42.3-66.9%) decrease in EC(50), whereas the percentage-transformed PD model demonstrated a 53.5% (42.7-64.3%) shift. It is concluded from these studies that there is a synergistic PD interaction between pregabalin and sildenafil.
Asunto(s)
Analgésicos/farmacología , Hiperalgesia/fisiopatología , Dolor/fisiopatología , Piperazinas/farmacología , Sulfonas/farmacología , Ácido gamma-Aminobutírico/análogos & derivados , Analgésicos/farmacocinética , Animales , Canales de Calcio/metabolismo , Enfermedad Crónica , Interacciones Farmacológicas , Activación del Canal Iónico , Ligandos , Masculino , Modelos Biológicos , Umbral del Dolor/efectos de los fármacos , Inhibidores de Fosfodiesterasa 5 , Piperazinas/farmacocinética , Pregabalina , Purinas/farmacocinética , Purinas/farmacología , Ratas , Ratas Sprague-Dawley , Citrato de Sildenafil , Sulfonas/farmacocinética , Ácido gamma-Aminobutírico/farmacocinética , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Synthesis of a number of bicyclic five-membered ring derivatives of gabapentin led to the identification of two compounds, (-)-(11A) and (20A) which both had an excellent level of potency against alpha(2)delta and were profiled in an in vivo model of neuropathic pain.
Asunto(s)
Aminas/síntesis química , Aminoácidos/síntesis química , Compuestos Bicíclicos con Puentes/síntesis química , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácido gamma-Aminobutírico/síntesis química , Aminas/química , Aminas/farmacocinética , Aminoácidos/química , Aminoácidos/farmacocinética , Animales , Barrera Hematoencefálica/metabolismo , Compuestos Bicíclicos con Puentes/química , Compuestos Bicíclicos con Puentes/farmacocinética , Células CHO , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Gabapentina , Neuralgia/tratamiento farmacológico , Dimensión del Dolor , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
A range of 3-alkylated five-membered ring derivatives of Gabapentin were synthesized and several were found to have good levels of potency against the alpha2delta calcium subunit of a voltage-gated calcium channel. Two compounds were profiled in in vivo models of pain and anxiety.
Asunto(s)
Aminas/síntesis química , Aminoácidos/síntesis química , Ansiolíticos/síntesis química , Ácidos Ciclohexanocarboxílicos/síntesis química , Ciclopentanos/síntesis química , Ácido gamma-Aminobutírico/síntesis química , Aminas/química , Aminas/farmacología , Aminoácidos/química , Aminoácidos/farmacología , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Canales de Calcio/metabolismo , Carragenina/farmacología , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacología , Ciclopentanos/química , Ciclopentanos/farmacología , Gabapentina , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Ratas , Estereoisomerismo , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
A range of 3,4-alkylated five-membered ring derivatives of gabapentin were synthesised. One compound (21) had an excellent level of potency against alpha(2)delta and was profiled in in vivo models of pain and anxiety.
Asunto(s)
Aminas/química , Aminoácidos/síntesis química , Ansiolíticos/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Ciclopentanos/síntesis química , Ácido gamma-Aminobutírico/química , Aminas/síntesis química , Aminas/farmacocinética , Aminoácidos/química , Aminoácidos/farmacología , Animales , Ansiolíticos/química , Ansiolíticos/farmacocinética , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Ciclopentanos/química , Ciclopentanos/farmacología , Modelos Animales de Enfermedad , Gabapentina , Hiperalgesia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Ratas , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/farmacocinéticaRESUMEN
A series of oxadiazolone bioisosteres of pregabalin 1 and gabapentin 2 were prepared, and several were found to exhibit similar potency for the alpha(2)-delta subunit of voltage-gated calcium channels. Oxadiazolone 9 derived from 2 achieved low brain uptake but was nevertheless active in models of osteoarthritis. The high clearance associated with compound 9 was postulated to be a consequence of efflux by OAT and/or OCT, and was attenuated on co-administration with cimetidine or probenecid.
Asunto(s)
Aminas , Ácidos Ciclohexanocarboxílicos , Osteoartritis/tratamiento farmacológico , Oxadiazoles/química , Oxadiazoles/uso terapéutico , Ácido gamma-Aminobutírico/análogos & derivados , Animales , Encéfalo/metabolismo , Interacciones Farmacológicas , Quimioterapia Combinada , Gabapentina , Factores de Transcripción de Octámeros , Transportadores de Anión Orgánico , Oxadiazoles/farmacología , Pregabalina , RatasAsunto(s)
Analgésicos/farmacología , Canales de Calcio/fisiología , Dolor/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Aminas/química , Aminas/farmacología , Aminas/uso terapéutico , Analgésicos/química , Analgésicos/uso terapéutico , Animales , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Anticonvulsivantes/uso terapéutico , Canales de Calcio/genética , Canales de Calcio/metabolismo , Ácidos Carboxílicos/química , Ácidos Carboxílicos/farmacología , Ácidos Carboxílicos/uso terapéutico , Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacología , Ácidos Ciclohexanocarboxílicos/uso terapéutico , Gabapentina , Humanos , Ligandos , Ratones , Ratones Mutantes , Dolor/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Pregabalina , Profármacos/química , Profármacos/farmacología , Profármacos/uso terapéutico , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/farmacología , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
Pregabalin, a 3-substituted analogue of gamma-amino butyric acid has recently been approved for treatment of neuropathic pain. We have investigated the anatomical binding profile of [(3)H] pregabalin following chronic constriction injury (CCI) and compared this with alpha 2 delta 1 subunit expression using in situ hybridisation. We report here that the intensity and distribution pattern of [(3)H] pregabalin binding is altered in the ipsilateral dorsal horn following CCI and this is associated with a corresponding increase in alpha 2 delta 1 mRNA in the ipsilateral dorsal root ganglion (DRG). It is likely that increased DRG mRNA production leads to increased alpha 2 delta 1 protein production and subsequent transport by primary afferents to the dorsal horn. The increased expression of calcium channel subunits and protein in central terminals is interesting, given that abnormal activity within sensory nerves is likely to significantly contribute to the symptomatology of neuropathic pain. The upregulation of pregabalin binding sites in sensory nerve terminals may occur as part of the response to nerve damage in neuropathic pain patients, and therefore, preferential actions of pregabalin at these sites may contribute to its mechanism of action in man.
Asunto(s)
Neuralgia/tratamiento farmacológico , Nociceptores/efectos de los fármacos , Enfermedades del Sistema Nervioso Periférico/tratamiento farmacológico , Células del Asta Posterior/efectos de los fármacos , Ácido gamma-Aminobutírico/análogos & derivados , Vías Aferentes/efectos de los fármacos , Vías Aferentes/metabolismo , Analgésicos/metabolismo , Analgésicos/farmacología , Animales , Unión Competitiva/efectos de los fármacos , Unión Competitiva/fisiología , Bloqueadores de los Canales de Calcio/metabolismo , Bloqueadores de los Canales de Calcio/farmacología , Canales de Calcio/genética , Canales de Calcio Tipo L , Enfermedad Crónica/terapia , Desnervación , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/metabolismo , Ligadura/efectos adversos , Masculino , Neuralgia/metabolismo , Neuralgia/fisiopatología , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/metabolismo , Neuropéptidos/antagonistas & inhibidores , Neuropéptidos/metabolismo , Nociceptores/metabolismo , Enfermedades del Sistema Nervioso Periférico/metabolismo , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Células del Asta Posterior/metabolismo , Pregabalina , ARN Mensajero/efectos de los fármacos , ARN Mensajero/metabolismo , Ensayo de Unión Radioligante , Ratas , Ratas Sprague-Dawley , Tritio , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Neuropathic pain is a debilitating condition affecting millions of people around the world and is defined as pain that follows a lesion or dysfunction of the nervous system. This type of pain is difficult to treat, but the novel compounds pregabalin (Lyrica) and gabapentin (Neurontin) have proven clinical efficacy. Unlike traditional analgesics such as nonsteroidal antiinflammatory drugs or narcotics, these agents have no frank antiinflammatory actions and no effect on physiological pain. Although extensive preclinical studies have led to a number of suggestions, until recently their mechanism of action has not been clearly defined. Here, we describe studies on the analgesic effects of pregabalin in a mutant mouse containing a single-point mutation within the gene encoding a specific auxiliary subunit protein (alpha2-delta-1) of voltage-dependent calcium channels. The mice demonstrate normal pain phenotypes and typical responses to other analgesic drugs. We show that the mutation leads to a significant reduction in the binding affinity of pregabalin in the brain and spinal cord and the loss of its analgesic efficacy. These studies show conclusively that the analgesic actions of pregabalin are mediated through the alpha2-delta-1 subunit of voltage-gated calcium channels and establish this subunit as a therapeutic target for pain control.
Asunto(s)
Analgésicos/uso terapéutico , Canales de Calcio/metabolismo , Dolor/tratamiento farmacológico , Dolor/metabolismo , Ácido gamma-Aminobutírico/análogos & derivados , Secuencia de Aminoácidos , Animales , Arginina/genética , Arginina/metabolismo , Autorradiografía , Secuencia de Bases , Canales de Calcio/química , Canales de Calcio/genética , Canales de Calcio Tipo N/metabolismo , Línea Celular , Chlorocebus aethiops , Constricción Patológica , Femenino , Formaldehído , Activación del Canal Iónico/efectos de los fármacos , Masculino , Ratones , Ratones Transgénicos , Mutación/genética , Dolor/genética , Pregabalina , Unión Proteica , Subunidades de Proteína/química , Subunidades de Proteína/genética , Subunidades de Proteína/metabolismo , Porcinos , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/uso terapéuticoRESUMEN
A series of carboxylate bioisosteres of structures related to gabapentin 1 have been prepared. When the carboxylate was replaced by a tetrazole, this group was recognized by the alpha2-delta protein. Further characterization of alpha2-delta binding compounds 14a and 14b revealed a similar pattern of functional in vitro and in vivo activity to gabapentin 1.
Asunto(s)
Aminas/síntesis química , Aminas/farmacología , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Ácidos Carboxílicos/química , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/farmacología , Tetrazoles/química , Ácido gamma-Aminobutírico/síntesis química , Ácido gamma-Aminobutírico/farmacología , Aminas/química , Animales , Anticonvulsivantes/síntesis química , Ácidos Ciclohexanocarboxílicos/química , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Evaluación Preclínica de Medicamentos , Gabapentina , Técnicas In Vitro , Ratones , Ratones Endogámicos DBA , Estructura Molecular , Ratas , Estereoisomerismo , Relación Estructura-Actividad , Ácido gamma-Aminobutírico/químicaRESUMEN
Pregabalin exhibits robust activity in preclinical assays indicative of potential antiepileptic, anxiolytic, and antihyperalgesic clinical efficacy. It binds with high affinity to the alpha(2)-delta subunit of voltage-gated calcium channels and is a substrate of the system L neutral amino acid transporter. A series of pregabalin analogues were prepared and evaluated for their alpha(2)-delta binding affinity as demonstrated by their ability to inhibit binding of [(3)H]gabapentin to pig brain membranes and for their potency to inhibit the uptake of [(3)H]leucine into CHO cells, a measure of their ability to compete with the endogenous substrate at the system L transporter. Compounds were also assessed in vivo for their ability to promote anxiolytic, analgesic, and anticonvulsant actions. These studies suggest that distinct structure activity relationships exist for alpha(2)-delta binding and system L transport inhibition. However, both interactions appear to play an important role in the in vivo profile of these compounds.
Asunto(s)
Sistema de Transporte de Aminoácidos L/metabolismo , Analgésicos/síntesis química , Ansiolíticos/síntesis química , Anticonvulsivantes/síntesis química , Canales de Calcio/metabolismo , Ácido gamma-Aminobutírico/análogos & derivados , Ácido gamma-Aminobutírico/síntesis química , Aminas/antagonistas & inhibidores , Aminas/metabolismo , Analgésicos/química , Analgésicos/farmacología , Animales , Ansiolíticos/química , Ansiolíticos/farmacología , Anticonvulsivantes/química , Anticonvulsivantes/farmacología , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/antagonistas & inhibidores , Ácidos Ciclohexanocarboxílicos/metabolismo , Gabapentina , Técnicas In Vitro , Leucina/antagonistas & inhibidores , Leucina/metabolismo , Masculino , Ratones , Ratones Endogámicos DBA , Pregabalina , Unión Proteica , Subunidades de Proteína/metabolismo , Ratas , Relación Estructura-Actividad , Porcinos , Ácido gamma-Aminobutírico/química , Ácido gamma-Aminobutírico/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
Osteoarthritis (OA) is a widespread condition affecting the elderly population. One of the most prominent features but least studied symptoms is chronic pain associated with OA. The study objective was to determine pain endpoints in rats with monosodium iodoacetate (MIA) induced OA, and to investigate the efficacy of common nociceptive agents. Sprague-Dawley rats received an intraarticular injection of either 25 microl 80 mg/ml MIA or 25 microl 0.9% sterile saline into the right knee joint. Changes in von Frey thresholds and latencies to stroking with a cotton bud (punctate and dynamic allodynia, respectively) were measured pre- and for up to 10 weeks post-intraarticular injection. Changes in hind paw weight distribution were also determined. Both punctate allodynia and a weight bearing deficit were observed in MIA-treated rats for up to 10 weeks. Interestingly, dynamic allodynia was not detected at any time point tested. Morphine (0.3-3 mg/kg, s.c.) and tramadol (3-100 mg/kg, p.o.) dose-dependently inhibited punctate allodynia and partially reversed weight bearing deficit. In conclusion, the MIA model of OA is reproducible and mimics OA pain in humans. Analgesic drug studies indicate this model may be useful for investigating chronic nociceptive pain.
Asunto(s)
Modelos Animales de Enfermedad , Yodoacetatos , Osteoartritis/inducido químicamente , Dolor/fisiopatología , Análisis de Varianza , Animales , Enfermedad Crónica , Inhibidores Enzimáticos , Lateralidad Funcional , Hiperalgesia/fisiopatología , Masculino , Morfina/uso terapéutico , Osteoartritis/tratamiento farmacológico , Osteoartritis/fisiopatología , Dolor/tratamiento farmacológico , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Factores de Tiempo , Soporte de Peso/fisiologíaRESUMEN
The present study examines the effect of combinations of gabapentin (Neurontin) and a selective neurokinin (NK)(1) receptor antagonist, 1-(1H-indol-3-ylmethyl)-1-methyl-2-oxo-2-[(1-phenylethyl)amino]ethyl]-2-benzofuranylmethyl ester (CI-1021), in two models of neuropathic pain. Dose responses to both gabapentin and CI-1021 were performed against static allodynia induced in the streptozocin and chronic constriction injury (CCI) models. Theoretical additive lines were calculated from these data. Dose responses to various fixed dose ratios of a gabapentin/CI-1021 combination were then examined in both models. In the streptozocin model, administration of gabapentin/CI-1021 combinations at fixed dose ratios of 1:1 and 60:1 resulted in an additive effect with dose response similar to the theoretical additive line. However, a synergistic interaction was seen after fixed dose ratios of 10:1, 20:1, and 40:1 with static allodynia completely blocked and the dose responses shifted approximately 8-, 30-, and 10-fold leftward, respectively, from the theoretical additive values. In the CCI model, after fixed dose ratios of 5:1 and 20:1, combinations of gabapentin and CI-1021 produced an additive response. At the fixed dose ratio of 10:1 static allodynia was completely blocked with an approximate 10-fold leftward shift of the dose response from the theoretical additive value, indicating synergy. The combination of gabapentin with a structurally unrelated NK(1) receptor antagonist, (2S,3S)-3-(2-methoxybenzylamino)-2-phenylpiperidine (CP-99,994), also produced synergy, at a fixed dose ratio of 20:1. This ratio completely blocked streptozocin-induced static allodynia and was approximately shifted leftward 5-fold from the theoretical additive value. These data suggest a synergistic interaction between gabapentin and NK(1) receptor antagonists in animal models of neuropathic pain.