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 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.
['Korkutata|Mustafa|M|', 'Saitoh|Tsuyoshi|T|', 'Cherasse|Yoan|Y|', 'Ioka|Shuji|S|', 'Duo|Feng|F|', 'Qin|Rujie|R|', 'Murakoshi|Nobuyuki|N|', 'Fujii|Shinya|S|', 'Zhou|Xuzhao|X|', 'Sugiyama|Fumihiro|F|', 'Chen|Jiang-Fan|JF|', 'Kumagai|Hidetoshi|H|', 'Nagase|Hiroshi|H|', 'Lazarus|Michael|M|']
D000241:Adenosine D058908:Adenosine A2 Receptor Agonists D000494:Allosteric Regulation D000818:Animals D001794:Blood Pressure D001831:Body Temperature D016466:CHO Cells D003412:Cricetulus D004353:Drug Evaluation, Preclinical D006339:Heart Rate D006993:Hypnotics and Sedatives D008297:Male D008810:Mice, Inbred C57BL D018345:Mice, Knockout D010627:Phenethylamines D011897:Random Allocation D043705:Receptor, Adenosine A2A D015398:Signal Transduction D000077310:Sleep, Slow-Wave D014851:Wakefulness
Body temperature Cardiovascular function Insomnia Allosteric modulator Adenosine A(2A) receptor Slow-wavesleep