The orexin system includes the neuropeptides orexin-A and -B and the cognate receptors of orexin-1 (OX1) and -2 (OX2) and has been indicated in a number of important physiological processes. It is generally accepted that the OX1 receptor is mainly involved in motivation and reward and the OX2 receptor in the modulation of sleep/wake cycle and energy homeostasis. A variety of OX1 selective antagonists (1-SORAs) have been disclosed in the literature and some of them have been evaluated as potential therapeutics for addiction treatment. In this review we summarize all OX1 antagonists reported thus far based on their core structure. Several dual orexin receptor antagonists (DORAs) and OX2 selective antagonist (2-SORAs) have also been recently evaluated in reward and addiction models. While DORAs may seem pharmacologically advantageous for alcohol addiction given the recent findings on the OX2 receptor in reward and alcohol consumption, 1-SORAs are the better options for other drugs of addiction such as cocaine due to the absence of the sedative effects inherently associated with dual antagonists.
