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_2AR) agonists strongly induce sleep, their cardiovascular effects preclude their use in treating sleep disorders. Enhancing endogenous A_2AR 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_2AR positive allosteric modulator (PAM)-1, enhanced adenosine signaling at the A_2AR 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_2AR KO mice. In contrast to the A_2AR agonist CGS 21680, the A_2AR PAM-1 did not affect blood pressure or heart rate. These findings indicate that enhancing A_2AR signaling promotes SWS without cardiovascular effects. Therefore, small molecules that allosterically modulate A_2ARs could help people with insomnia to fall asleep.

失眠是最常见的睡眠问题之一，在一般人群中患病率估计为10％至15％。尽管腺苷A _2A受体（A _2A R）激动剂强烈诱导睡眠，但它们的心血管作用使它们无法用于治疗睡眠障碍。但是，增强内源性A _2A R信号传导可能是治疗失眠的另一种策略，因为大脑的腺苷水平在清醒期间会积聚。在本研究中，我们发现3,4-二氟-2-（（（2-氟-4-碘代苯基）氨基）苯甲酸，表示为A _2A R正变构调节剂（PAM）-1，在A处增强了腺苷信号传导。_2A腹膜内给药后，R和诱导的慢波睡眠（SWS）不会影响野生型雄性小鼠的体温，而在A _2A R KO小鼠中消除了这种苯甲酸衍生物的SWS诱导作用。与A _2A R激动剂CGS 21680相比，A _2A R PAM-1不影响血压或心率。这些发现表明，增强A _2A R信号传导可促进SWS发挥作用，而无心血管作用。因此，变构调节A _2A Rs的小分子可以帮助失眠的人入睡。