These compounds have been profiled further, and show >5000-fold selectivity over OX1R. Results: ORX-849 and related compounds behaved as a potent, full agonists at OX2R relative to the native ligand orexin-A (OXA) in the FLIPR assay.

Electroencephalogram (EEG), electromyogram (EMG), and video recordings are used in Atax mice during their active phase to evaluate effects on arousal states and cataplexy. In vivo efficacy in enhancing wakefulness is evaluated in wild type (WT) and Atax mice during their rest phase using Piezo Sleep, a rapid non-invasive method for classifying sleep and wakefulness by unsupervised machine learning based on physiologically relevant readouts. Electrophysiological recordings are performed on brain slices from the ventral tuberomammillary nucleus (TMN) in mouse hypothalamus. Methods: In vitro calcium mobilization (FLIPR), β-arrestin and inositol-phosphate accumulation assays are performed in Chinese hamster ovary cells stably expressing human recombinant OX2R or orexin receptor 1 (OX1R). Here we present the profile of ORX-849, an early prototype oral orexin receptor 2 (OX2R) agonist, and other novel selective OX2R agonists developed using structure-based drug design with an OX2R stabilized receptor (StaR®) protein and high-resolution protein crystallography. The orexin/ataxin-3 (Atax) mouse recapitulates the orexin neurodegeneration of NT1, exhibiting cataplexy episodes and decreased wakefulness. Objectives/Introduction: Narcolepsy Type 1 (NT1) is caused by the profound loss of orexin-producing neurons, resulting in dysregulation of sleep/wake and energy homeostasis. Hartman 1 1Orexia Therapeutics, a Centessa Company, Altrincham, Cheshire, United Kingdom, 2Sosei Heptares, Great Abington, Cambridge, United Kingdom 1: PHARMACOLOGY AND BIOCHEMISTRY P001 Novel orexin receptor-2 agonists developed using structure-based drug design: Prototype compounds promote wakefulness and reduce cataplexy in orexin/ataxin-3 and wt mice S.W.

Novas Got Nerve by B.L. Jones