TCS-1102 (DORA-1) is a high-affinity (Ki = 3 nM against [3H]-TCS-1102 for binding hOX1R and Ki = 0.2 nM against [3H]-pyrrolylphenyl analog for binding hOX2R) dual orexin receptor antagonist (DORA) that potently inhibits calcium mobilization in hOX1R & hOX2R CHO transfectants (IC50 = 17 & 4 nM, respectively). TCS-1102 promotes sleep (50-100 mg/kg p.o.), decreases fear/anxiety (10-20 mg/kg i.p.), and inhibits ADL-orexin B peptide-induced locomotion (by 56%/74%/100% with 15/50/100 mg/kg i.p. 30 min before ADL-XB ICV injection) with good pharmacokinetic properties, brain penetration (Brain/plasma conc. = 2.37 μM/3.50 μM 3 hrs post 100 mg/kg i.p.), and oral availability (Cmax/AUC(0–24h) = 1.21 μM/6.8 μM h and 3.01 μM/12.5 μM h, respectively post 50 and 100 mg/kg p.o. dosage) in rats in vivo.
The ventrolateral preoptic area (VLPO) and the orexin/hypocretin neuronal system are key regulators of sleep onset, transitions between vigilance states, and energy homeostasis. Reciprocal projections exist between the VLPO and orexin/hypocretin neurons. Although the importance of the VLPO to sleep
Orexin (hypocretin) neurons located in the posterior hypothalamus send projections to multiple areas of the brain involved in arousal and experimental evidence indicates that these neurons play a role in the physiological and behavioral responses to stress. This study was
Nature chemical biology, 13(2), 235-242 (2016-12-20)
Understanding the pharmacological similarity of G protein-coupled receptors (GPCRs) is paramount for predicting ligand off-target effects, drug repurposing, and ligand discovery for orphan receptors. Phylogenetic relationships do not always correctly capture pharmacological similarity. Previous family-wide attempts to define pharmacological relationships
Frontiers in pharmacology, 6, 257-257 (2015-11-19)
Sleep-wake states are impaired in various neurological disorders. Impairment of sleep-wake states can be an early condition that exacerbates these disorders. Therefore, treating sleep-wake dysfunction may prevent or slow the development of these diseases. Although many gene products are likely
A series of OX(2)R/OX(1)R dual orexin antagonists was prepared based on a proline bis-amide identified as a screening lead. Through a combination of classical and library synthesis, potency enhancing replacements for both amide portions were discovered. N-methylation of the benzimidazole
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