TCS-1102 (C15-1722-977)

Biochem/physiol Actions

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.