0049 Orexin 2 receptor agonist activates pre-Bötzinger complex neurons, phrenic motoneurons and the diaphragm in rodents

Abstract Introduction Neurons in the pre-Bötzinger complex are critical for generation of inspiratory rhythm and regulation activity phrenic motoneurons, which control diaphragm. Dysregulation this neuronal network resulting dysfunction diaphragm is associated with central sleep apnea (CSA). Orexins by stimulating both orexin 1 receptor (OX1R) and/or 2 (OX2R) can activate these neurons In study, we assessed effects OX2R-selective agonists on complex, Methods danavorexton (TAK-925) OX-201 (a tool compound longer plasma half-life than rodents) were used. OX2R OX1R agonistic activities examined calcium mobilization assay hOX2R/CHO-K1 cells hOX1R/CHO-K1 cells, respectively. Activity motoneurons was investigated electrophysiological recording rat tissues. evaluated electromyogram anesthetized rats. Respiratory whole-body plethysmography mice. Results Danavorexton showed potent 50% effective concentration (EC50) values 5.5 nM 8.0 nM, had >5,000-fold 1,000-fold selectivity over OX1R, vitro analyses, increased burst frequency (EC50: 300 760 respectively) 1.6 µM not determined, respectively). Intravenous administration at 3 mg/kg rats oral respiratory conscious Conclusion may enhance function via activation through stimulation motoneurons. have therapeutic potential patients CSA if enhancement be observed non-arousal concentrations. Further preclinical clinical studies worth conducting CSA. Support (if any) This work conducted Takeda Pharmaceutical Company Limited.