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Objective: Insomnia is one of the most common sleep problems with an estimated prevalence of 10% to 15% in the general population. Although adenosine A2A receptor (A2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A2AR signaling, however, may be an alternative strategy for treating insomnia, because adenosine levels in the brain accumulate during wakefulness. Methods: We established A2AR-expressing Chinese hamster ovary cells to measure cAMP produced upon A2AR activation by using a fluorescence resonance energy transfer immunoassay. Subsequently, we screened several thousand small-molecule compounds for allosteric effects at A2AR in the cell-culture bioassay. Results: We identified a positive allosteric modulator for A2AR, termed A2AR PAM-1. When we examined the sleep-inducing activity of A2AR PAM-1 by monitoring the electroencephalogram, we found that the intraperitoneal (IP) administration of A2AR PAM-1 dose dependently (30-75 mg/kg) increased the total amount of slow wave sleep (SWS). In addition, the SWSinducing effect of A2AR PAM-1 was suppressed by A2AR antagonist ZM241385 (15 mg/kg, IP) and abolished in A2AR knockout mice. In contrast to A2AR agonist CGS 21680, blood pressure measured by using an electrosphygmomanometer and heart rate monitored by using telemetry transmitters were not affected after IP administration of A2AR PAM-1. Conclusion: Small molecules like the A2AR allosteric modulator A2AR PAM-1 may help people with sleep problems to fall asleep. [ABSTRACT FROM AUTHOR]