Enhancing endogenous adenosine A 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 receptor (AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous AR 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 AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the AR 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 AR KO mice. In contrast to the AR agonist CGS 21680, the AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate ARs could help people with insomnia to fall asleep.