LSN2424100: a novel, potent orexin-2 receptor antagonist with selectivity over orexin-1 receptors and activity in an animal model predictive of antidepressant-like efficacy.
We describe a novel, potent and selective orexin-2 (OX2)/hypocretin-2 receptor antagonist with in vivo activity in an animal model predictive of antidepressant-like efficacy. N-biphenyl-2-yl-4-fluoro-N-(1H-imidazol-2-ylmethyl) benzenesulfonamide HCl (LSN2424100) binds with high affinity to recombinant human OX2 receptors (Ki = 4.5 nM), and selectivity over OX1 receptors (Ki = 393 nM). LSN2424100 inhibited OXA-stimulated intracellular calcium release in HEK293 cells expressing human and rat OX2 receptors (Kb = 0.44 and 0.83 nM, respectively) preferentially over cells expressing human and rat OX1 (Kb = 90 and 175 nM, respectively). LSN2424100 exhibits good exposure in Sprague-Dawley rats after IP, but not PO, administration of a 30 mg/kg dose (AUC0-6 h = 1300 and 269 ng(*)h/mL, respectively). After IP administration in rats and mice, LSN2424100 produces dose-dependent antidepressant-like activity in the delayed-reinforcement of low-rate (DRL) assay, a model predictive of antidepressant-like efficacy. Efficacy in the DRL model was lost in mice lacking OX2, but not OX1 receptors, confirming OX2-specific activity. Importantly, antidepressant-like efficacy of the tricyclic antidepressant, imipramine, was maintained in both OX1 and OX2 receptor knock-out mice. In conclusion, the novel OX2 receptor antagonist, LSN2424100, is a valuable tool compound that can be used to explore the role of OX2 receptor-mediated signaling in mood disorders.
Lilly Research Laboratories, Department of Neuroscience, Eli Lilly and Company Indianapolis, IN, USA.
Thomas E
TE
Fitch
Lilly Research Laboratories, Department of Neuroscience, Eli Lilly and Company Indianapolis, IN, USA.
Mark J
MJ
Benvenga
Lilly Research Laboratories, Department of Neuroscience, Eli Lilly and Company Indianapolis, IN, USA.
Cynthia D
CD
Jesudason
Lilly Research Laboratories, Department of Neuroscience, Eli Lilly and Company Indianapolis, IN, USA.
Charity
C
Zink
Lilly Research Laboratories, Department of Neuroscience, Eli Lilly and Company Indianapolis, IN, USA.
Amy B
AB
Vandergriff
Lilly Research Laboratories, Department of Neuroscience, Eli Lilly and Company Indianapolis, IN, USA.
Michelle M
MM
Menezes
Lilly Research Laboratories, Department of Neuroscience, Eli Lilly and Company Indianapolis, IN, USA.
Douglas A
DA
Schober
Lilly Research Laboratories, Department of Neuroscience, Eli Lilly and Company Indianapolis, IN, USA.
Linda M
LM
Rorick-Kehn
DRL; OX2 antagonist; antidepressant; hypocretin; mouse; neuropeptide; orexin; rat