RESUMEN
Neuropathic pain is a debilitating, chronic condition with a significant unmet need for effective treatment options. Recent studies have demonstrated that in addition to neurons, non-neuronal cells such as microglia contribute to the initiation and maintenance of allodynia in rodent models of neuropathic pain. The Ca2+- activated K+ channel, KCa3.1 is critical for the activation of immune cells, including the CNS-resident microglia. In order to evaluate the role of KCa3.1 in the maintenance of mechanical allodynia following peripheral nerve injury, we used senicapoc, a stable and highly potent KCa3.1 inhibitor. In primary cultured microglia, senicapoc inhibited microglial nitric oxide and IL-1ß release. In vivo, senicapoc showed high CNS penetrance and when administered to rats with peripheral nerve injury, it significantly reversed tactile allodynia similar to the standard of care, gabapentin. In contrast to gabapentin, senicapoc achieved efficacy without any overt impact on locomotor activity. Together, the data demonstrate that the KCa3.1 inhibitor senicapoc is effective at reducing mechanical hypersensitivity in a rodent model of peripheral nerve injury.
Asunto(s)
Acetamidas/farmacología , Hiperalgesia/complicaciones , Hiperalgesia/tratamiento farmacológico , Canales de Potasio de Conductancia Intermedia Activados por el Calcio/antagonistas & inhibidores , Traumatismos de los Nervios Periféricos/complicaciones , Bloqueadores de los Canales de Potasio/farmacología , Compuestos de Tritilo/farmacología , Acetamidas/efectos adversos , Acetamidas/farmacocinética , Acetamidas/uso terapéutico , Animales , Células CHO , Cricetinae , Cricetulus , Relación Dosis-Respuesta a Droga , Estabilidad de Medicamentos , Humanos , Hiperalgesia/metabolismo , Hiperalgesia/fisiopatología , Locomoción/efectos de los fármacos , Microglía/efectos de los fármacos , Microglía/metabolismo , Potasio/metabolismo , Bloqueadores de los Canales de Potasio/efectos adversos , Bloqueadores de los Canales de Potasio/farmacocinética , Bloqueadores de los Canales de Potasio/uso terapéutico , Ratas , Compuestos de Tritilo/efectos adversos , Compuestos de Tritilo/farmacocinética , Compuestos de Tritilo/uso terapéuticoRESUMEN
The identification of the novel, selective, orally bioavailable Sortilin inhibitor AF38469 is described. Structure-activity relationships and syntheses are reported, along with an X-ray crystal structure of the sortilin-AF38469 protein-inhibitor complex.