Objective

The orexins, also known as hypocretins, are neuropeptides produced in neurones in hypothalamus and perifornical area which project widely throughout the brain. The peptides (OXA and OXB) act on the G protein coupled receptors orexin-1 (OX1R) and -2 (OX2R). Human post-mortem human data reveals a large increase (~50 %) in orexigenic neurons in the hypothalamus of opiate addicts versus healthy controls. In pre-clinical models of substance seeking and craving, activation of orexinergic neurons in the lateral hypothalamus can be observed when conditioned animals received drug cues. When reward seeking behaviour is extinguished it can be reinstated by administration of orexin-A and blocked by an OX1R antagonist. It is thought OX1R antagonists reduce motivation to self-administer drugs when high levels of effort are required, or when motivation for drug reward is augmented by the presence of external stimuli like drug-associated cues/contexts or stressors. As blockade of OX2R is known to induce hypnotic effects, it is important when targeting the reward system to develop selective OX1R antagonists. To aid structure-based drug design (SBDD) of selective OX1R antagonists the X-ray structures of OX1R and OX2R have been solved with a range of ligands and chemotypes using the StaR (Stabilised GPCR) technology. These structures have highlighted how selectivity between the receptors is achieved and has been used to optimise the affinity and selectivity of selective OX1 compounds.