Orexins are neuropeptides exclusively produced in the lateral hypothalamic areas. Orexin 1 receptor (OX1) and Orexin 2 receptor (OX2) are G-protein-coupled receptors that work together with orexins to regulate energy homeostasis, feeding and reward, and sleep-wake cycle. Almorexant is a dual OX1 and OX2 antagonist. It inhibited the binding of [125I]orexin-A to OX1 and OX2 overexpressed in CHO cells with IC50 values of 6.6 and 3.4nM, respectively. [3H]Almorexant binds to hOX1and hOX2 with Kd values of 1.3 and 0.17nM, respectively. Almorexant inhibited the binding of [3H]Almorexant to HEK293-hOX1 and -hOX2 cell membranes with Ki values of 4.7 and 0.9nM, respectively. Almorexant at 1μM antagonized orexin-A-induced increase of firing frequency of rat ventral tegmental area dopaminergic neurons[3]. The administration of Almorexant at 100mg/kg in a mouse binge-drinking model reduced ethanol intake compared to vehicle-treated controls. Almorexant at the doses of 50 and 100mg/kg also decreased the blood ethanol concentrations relative to the control mice[4].
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