Enhancing endogenous adenosine A2A receptor signaling induces slow-wave sleep without affecting body temperature and cardiovascular function

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.