Insomnia is one of the most common sleep disorders, affecting 10–15% of the global population. Because classical remedies used to treat insomnia have various side effects, new therapeutics for insomnia are attracting attention. In the present study, we found that N2-Ethyl-N4-(furan-2-ylmethyl) quinazoline-2,4-diamine (AR-001) has adenosine A1 receptor agonistic activity and exhibits hypnotic efficacy by decreasing sleep onset latency and increasing total sleep time in a pentobarbital-induced sleep model. This hypnotic effect of AR-001 was significantly inhibited by the adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dipropylxanthine (DPCPX). As a result of immunohistochemistry, AR-001 was shown to increase neural activity in the sleep-promoting region, ventrolateral preoptic nucleus (VLPO), and decrease neural activity in the wake-promoting region, basal forebrain (BF), and lateral hypothalamus (LH), and that these effects of AR-001 were significantly inhibited by DPCPX treatment. In addition, AR-001 increased adenosine A1 receptor mRNA levels in the hypothalamus. In conclusion, this study suggests that AR-001 has a hypnotic effect, at least partially, through adenosine A1 receptor and may have therapeutic potential for insomnia.
This work was partly supported by the GRRC program of Gyeonggi province (GRRCAjou2023-B01) and by Korea Initiative for fostering University of Research and Innovation Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. NRF2021M3H1A104892211) and by a grant (21153MFDS602) from the Ministry of Food and Drug Safety, Republic of Korea.The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Yi-Sook Jung reports financial support was provided by GRRC program of Gyeonggi province (GRRCAjou2023-B01). Hye Jin Jee reports was provided by Korea Initiative for fostering University of Research and Innovation Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. NRF2021M3H1A104892211). Yi-Sook Jung reports financial support was provided by Ministry of Food and Drug Safety, Republic of Korea (21153MFDS602). If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.This work was partly supported by the GRRC program of Gyeonggi province (GRRCAjou2023-B01) and by Korea Initiative for fostering University of Research and Innovation Program of the National Research Foundation (NRF) funded by the Korean government (MSIT) (No. NRF2021M3H1A104892211) and by a grant (21153MFDS602) from the Ministry of Food and Drug Safety, Republic of Korea.
