Recently, we identified a novel orexin 2 (OX ) receptor antagonist, SDM-878 (2-(3-(2-(1H-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.
The in vitro potency and selectivity of SDM-878 were examined in CHO cells that exhibit stable expression of human orexin 1 (OX ), human orexin 2 (OX ), rat OX , and rat OX 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 receptor agonist, ADL-OXB ([Ala , d-Leu ]-orexin B).
SDM-878 showed potent inhibitory activities for human and rat OX receptors with IC values of 10.6 and 8.8 nM, respectively, and approximately 1000-fold selectivity against the OX 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 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.
Our results suggest that SDM-878 is likely to be a good pharmacological tool for investigating the role of the OX receptor and may have therapeutic potential for the treatment of insomnia.

© 2020 Mochida Pharmaceutical Co., Ltd. Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsycho Pharmacology.