RESUMO
P2X3 receptor is an ATP-gated ion channel, mainly localized on peripheral sensory neurons. Currently, several clinical trials are being conducted with P2X3 receptor antagonists for the treatment of chronic pain or cough. To identify a P2X3 lead compound, we reexamined the HTS evaluation compounds and selected dioxotriazine derivatives from which we identified a hit compound. As a result of the hit-to-lead SAR, we obtained lead compound 1 which had a moderate inhibitory effect on P2X3 receptors (IC50, 128 nM). Further improvement of the potency and PK profiles of this lead compound finally led to the selected compound 74 (P2X3 IC50, 16.1 nM; P2X2/3 IC50, 2931 nM), which demonstrated a strong analgesic effect against allodynia on oral administration in the rat partial sciatic nerve ligation model of neuropathic pain (ED50, 3.1 mg/kg).
Assuntos
Neuralgia/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X3/metabolismo , Triazinas/farmacologia , Administração Oral , Animais , Relação Dose-Resposta a Droga , Humanos , Microssomos Hepáticos/química , Microssomos Hepáticos/metabolismo , Estrutura Molecular , Neuralgia/metabolismo , Antagonistas do Receptor Purinérgico P2X/administração & dosagem , Antagonistas do Receptor Purinérgico P2X/química , Ratos , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/químicaRESUMO
Grit, defined as perseverance of effort and consistency of interest, has attracted attention as a predictor of success in various fields beyond IQ and the Big Five personality dimension of Conscientiousness. The purpose of the current study was to examine previously uninvestigated questions regarding grit using a cross-sectional design among a large number of working adults in Japan. First, we tested geographical generalizability of associations between grit and orientations towards happiness by comparing previous studies in the U.S. and the current study in Japan. It was confirmed that orientation towards meaning rather than orientation towards engagement had a stronger positive correlation with grit in our sample of Japanese people. This result is inconsistent with previous studies in the U.S. Furthermore, the Big Five dimension of Openness to Experience was newly confirmed as having a positive association with grit. Second, we examined the association between grit and work engagement, which is considered as an outcome indicator for work performance. In this analysis, grit was a strong predictor for work performance as well as academic performance.
