Insomnia is one of the most common sleep problems with an estimated prevalence of 10%–15% in the general population. Although adenosine A 2A receptor (A 2A R) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A 2A R 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 A 2A R positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A 2A R 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 A 2A R KO mice. In contrast to the A 2A R agonist CGS 21680, the A 2A R PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A 2A R signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A 2A Rs could help people with insomnia to fall asleep.