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Aims  Recently, we identified a novel orexin 2 (OX 2 ) receptor antagonist, SDM‐878 (2‐(3‐(2‐(1 H ‐pyrazol‐1‐yl)nicotinoyl)‐3,8‐diazabicyclo[3.2.1]octan‐8‐yl)‐3‐methoxyisonicotinonitrile). The purpose of the present study is to characterize the in vitro and in vivo pharmacological effects of SDM‐878.    Methods  The in vitro potency and selectivity of SDM‐878 were examined in CHO cells that exhibit stable expression of human orexin 1 (OX 1 ), human orexin 2 (OX 2 ), rat OX 1 , and rat OX 2 receptors. Then, the plasma half‐life, oral bioavailability, and brain penetration of SDM‐878 were examined in rats. The in vivo effect of SDM‐878 in rats was tested using electroencephalography (EEG). The target engagement of SDM‐878 in the rat brain was examined using the antagonistic effect against hyperlocomotion caused by the intracerebroventricular administration of the OX 2  receptor agonist, ADL‐OXB ([Ala 11 , d‐Leu 15 ]‐orexin B).    Results  SDM‐878 showed potent inhibitory activities for human and rat OX 2  receptors with IC values of 10.6 and 8.8 nM, respectively, and approximately 1000‐fold selectivity against the OX 1 receptor. In rat studies, SDM‐878 exhibited a relatively short half‐life in plasma, oral bioavailability, and good brain penetration. These data indicate that SDM‐878 is a potent, selective, orally active, and brain‐penetrable OX 2 receptor antagonist. In behavioral studies using rats, SDM‐878 (100 mg/kg) antagonized hyperlocomotion caused by intracerebroventricular administration of ADL‐OXB. SDM‐878 exhibited a potent sleep‐promoting effect at the same dose (100 mg/kg) in a rat EEG study.    Conclusion  Our results suggest that SDM‐878 is likely to be a good pharmacological tool for investigating the role of the OX 2 receptor and may have therapeutic potential for the treatment of insomnia.

Pharmacological characterization of a novel potent, selective, and orally active orexin 2 receptor antagonist, SDM‐878