Highlighted Papers Selective Orexin-1 Receptor Antagonist Attenuates Stress-Induced Hyperarousal

A role for the orexin-1 receptor (OX1R) in emotional behavior is emerging. The present study characterizes the brain-penetrant OX1R antagonist, compound 56 [N-({3-[(3-ethoxy-6-methylpyridin2-yl)carbonyl]-3-azabicyclo[4.1.0]hept-4-yl}methyl)-5-(trifluoromethyl) pyrimidin-2-amine]. Receptor binding studies demonstrated that compound 56 crossed the blood-brain barrier and occupied OX1Rs in the rat brain. While compound 56 did not alter sleep in wild-type mice, its administration in OX2R knockout mice selectively promoted rapid eye movement sleep, demonstrating target engagement. In a rat model of stress induced by cage exchange, the OX1R antagonist prevented prolongation of sleep onset without affecting sleep duration. In a rat model of panic vulnerability (involving disinhibition of the perifornical OX region), the compound attenuated sodium lactate–induced panic-like behaviors without altering baseline locomotor or autonomic activity. In conclusion, OX1R antagonism represents a novel therapeutic strategy for the treatment of various psychiatric disorders associated with stress.