In 1998, De Lecea and Sakurai independently reported the existence of the orexin neuropeptides hypocretin-1 (hcrt-1) and hypocretin-2 (hcrt-2) which were also termed orexin-A and orexin-B. These neuropeptides were shown to originate in the hypothalamus from a common precursor and project widely to key areas of the central nervous system (CNS) hypothesized to control sleep-wake states, modulation of food intake, panic, anxiety, reward and addictive behaviors. The orexin neuropeptides mediate their effect by stimulating two distinct G-protein coupled receptors, orexin-1 (OX1) and orexin-2 (OX2).  These receptors are co-located or selectively located in certain areas of the CNS suggesting differentiated roles. For example, OX1Rs are selectively expressed in the bed nucleus of the stria terminalis, amygdala, cingulate cortex and locus coeruleus which play a role in panic and anxiety. Conversely, OX2Rs are exclusively expressed in histaminergic neurons in the tuberomammillary nuclei which play a critical role in wake promotion.  Interest in the orexin system has led to at least four dual orexin receptor antagonists entering human trials for the treatment of sleep related disorders. We have shown pre-clinically that selective antagonism of the OX2R is sufficient to initiate and prolong sleep in rodents. Selectively targeting the OX1R and its role in more complex emotional behavior (panic, anxiety) is now emerging.  For example, sodium lactate infusion or acute hypercapnia, which causes panic in humans and are used as an animal model of panic, activates orexin neurons in the perifornical hypothalamus. This activation correlates with anxiety in the social interaction test or open field test. Blocking the activation with either siRNA or selective OX1 receptor antagonists attenuates these panic-like responses.   In order to further validate the role of the OX1 receptor, characterization of improved tool compounds in animal models is required.  Presented here will be the discovery, synthetic methods and SAR associated with novel selective orexin receptor antagonists.

Discovery and characterization of selective orexin receptor antagonists

248th National Meeting (2014)

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