Small molecule orexin agonist ROXA-47 enhances learning and memory in mice

Aging affects multiple physiological functions including physical activity behavior, the sleep-wake cycle, and cognition, processes which are regulated in part by lateral hypothalamic orexin neurons. Loss of orexin peptides and neurons is associated with aging, as well as conditions such as type-1 narcolepsy, which are characterized by altered cognitive function. Direct brain administration of orexin-A improves cognitive function; however, the cognitive effects of orexin agonists delivered systemically have not been studied, in part due to the lack of small molecule agonists suitable for systemic administration. In this study, we developed a metabolically stable small molecule dual agonist ROXA-47 with low nanomolar potencies at both OX1R and OX2R. The effects on cognition of ROXA-47 and a previously reported OX2R agonist YNT-185 were measured by peripheral injections in 6 mo. and 12-mo. old mice using two-way active avoidance (TWAA) and/or the contextual object recognition task (CORT). To determine the individual receptor effect of ROXA-47 on TWAA and CORT memory, OX1R (SB-334867) or OX2R (JNJ-10397049) antagonists (5 mg/kg, i.p.) were injected prior to ROXA-47 (40 mg/kg, i.p.). ROXA-47 and YNT-185 decreased latency and increased total responses in the TWAA, while both ROXA-47 and YNT-185 enhanced discrimination index in the CORT, indicating improved cognition in 6 mo. old and 12-mo. old mice. ROXA-47-enhanced TWAA and CORT memory was attenuated by SB334867 but not JNJ-10397049, suggesting that ROXA-47 improves cognitive function in mice primarily via OX1R activation. These results suggest that small molecule orexin agonists may have therapeutic potential for age-related cognitive decline.