LAUSR

&NA; Insomnia is one of the most common sleep problems with an estimated prevalence of 10%–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. In the present study, we found that 3,4‐difluoro‐2‐((2‐fluoro‐4‐iodophenyl)amino)benzoic acid, denoted A2AR positive allosteric modulator (PAM)‐1, enhanced adenosine signaling at the A2AR and induced slow wave sleep (SWS) without affecting body temperature in wild‐type male mice after intraperitoneal administration, whereas the SWS‐inducing effect of this benzoic acid derivative was abolished in A2AR KO mice. In contrast to the A2AR agonist CGS 21680, the A2AR PAM‐1 did not affect blood pressure or heart rate. These findings indicate that enhancing A2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A2ARs could help people with insomnia to fall asleep. HIGHLIGHTSFirst positive allosteric modulator for adenosine A2A receptors, denoted A2AR PAM‐1.A2AR PAM‐1 promotes slow‐wave sleep (SWS) in a dose‐dependent manner in mice.Adenosine A2A receptors are necessary for A2AR PAM‐1 to induce SWS.Enhancing adenosine A2A receptor signaling does not induce hypothermia.Systemic administration of A2AR PAM‐1 does not affect blood pressure or heart rate.