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Abstract 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. Graphical abstract Image 1 Highlights • First positive allosteric modulator for adenosine A 2A receptors, denoted A 2A R PAM-1. • A 2A R PAM-1 promotes slow-wave sleep (SWS) in a dose-dependent manner in mice. • Adenosine A 2A receptors are necessary for A 2A R PAM-1 to induce SWS. • Enhancing adenosine A 2A receptor signaling does not induce hypothermia. • Systemic administration of A 2A R PAM-1 does not affect blood pressure or heart rate. [ABSTRACT FROM AUTHOR]

Background: Insomnia is associated with psychiatric illnesses such as bipolar disorder or schizophrenia. Treating insomnia improves psychotic symptoms severity, quality of life, and functional outcomes. Patients with psychiatric disorders are often dissatisfied with the available therapeutic options for their insomnia. In contrast, positive allosteric modulation of adenosine A 2A receptors (A 2A Rs) leads to slow-wave sleep without cardiovascular side effects in contrast to A 2A R agonists. Methods: We investigated the hypnotic effects of A 2A R positive allosteric modulators (PAMs) in mice with mania-like behavior produced by ablating GABAergic neurons in the ventral medial midbrain/pons area and in a mouse model of schizophrenia by knocking out of microtubule-associated protein 6. We also compared the properties of sleep induced by A 2A R PAMs in mice with mania-like behavior with those induced by DORA-22, a dual orexin receptor antagonist that improves sleep in pre-clinical models, and the benzodiazepine diazepam. Results: A 2A R PAMs suppress insomnia associated with mania- or schizophrenia-like behaviors in mice. A 2A R PAM-mediated suppression of insomnia in mice with mania-like behavior was similar to that mediated by DORA-22, and, unlike diazepam, did not result in abnormal sleep. Conclusion: A 2A R allosteric modulation may represent a new therapeutic avenue for sleep disruption associated with bipolar disorder or psychosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lin, Roy, Ioka, Otani, Amezawa, Ishikawa, Cherasse, Kaushik, Klewe-Nebenius, Zhou, Yanagisawa, Oishi, Saitoh and Lazarus.)

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., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Five new firefly luciferin (1) analogues were synthesized and their light emission properties were examined. Modifications of the thiazoline moiety in 1 were employed to produce analogues containing acyclic amino acid side chains (2-4) and heterocyclic rings derived from amino acids (5 and 6) linked to the benzothiazole moiety. Although methyl esters of all of the synthetic derivatives exhibited chemiluminescence activity, only carboluciferin (6), possessing a pyrroline-substituted benzothiazole structure, had bioluminescence (BL) activity (λmax =547 nm). Results of bioluminescence studies with AMP-carboluciferin (AMP=adenosine monophosphate) and AMP-firefly luciferin showed that the nature of the thiazoline mimicking moiety affected the adenylation step of the luciferin-luciferase reaction required for production of potent BL. In addition, BL of 6 in living mice differed from that of 1 in that its luminescence decay rate was slower., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)