title: WS0701: a novel sedative-hypnotic agent acting on the adenosine system.
abstract: To characterize the sedative and hypnotic profile of the novel adenosine derivative ((3S,4R,5R)-3,4-dihydroxy-5-(6-((4-hydroxy-3-methoxybenzyl)amino)-9H-purin-9-yl)tetrahydrofuran-2-yl) methyl diaconate (WS0701), we performed a variety of behavioural tests and investigated the influence of WS0701 on various sleep stages. In mice, WS0701 significantly increased the number of entries and time spent in open arms in the elevated plus maze test, indicating an anxiolytic effect. WS0701 decreased locomotor activity counts and head dips in the hole-board test and enhanced sodium pentobarbital-induced hypnosis. However, WS0701 did not induce the loss of the righting reflex or amnesic effects in behavioural models. In rats, WS0701 exerted a sedative effect and markedly prolonged the time spent in non-rapid-eye-movement sleep, especially slow-wave sleep, but reduced the time spent in rapid-eye-movement sleep (REMS). Pretreatment with the selective adenosine A2a receptor antagonist SCH58261 attenuated the sedative and hypnotic effects of WS0701. WS0701 did not protect mice against picrotoxin-induced seizures, but inhibited adenosine deaminase activity and increased adenosine levels in the frontal cortex and hypothalamus of mice. In conclusion, WS0701 shows anxiolytic, sedative as well as sleep stage alterative effects, which may be related to the adenosine system.
authors.affiliation: aBeijing Key Laboratory of Drug Targets Identification and Drug Screening bState Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College cDepartment of Pharmacology, Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Beijing dWeifang Traditional Chinese Medicine Hospital, Shan Dong, China.
authors.forename: Xiao-Yu
authors.initials: XY
authors.lastname: Bai
authors.forename: Xue-Qiong
authors.initials: XQ
authors.lastname: Zhang
authors.forename: Yong-He
authors.initials: YH
authors.lastname: Zhang
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.forename: Ling-Hua
authors.initials: LH
authors.lastname: Hao
authors.forename: Rui
authors.initials: R
authors.lastname: Liu
authors.forename: Zhong-Lin
authors.initials: ZL
authors.lastname: Huang
authors.forename: Wei-Ku
authors.initials: WK
authors.lastname: Zhang
authors.forename: Zong-Miao
authors.initials: ZM
authors.lastname: Sun
authors.forename: Guan-Hua
authors.initials: GH
authors.lastname: Du
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D003651:Decanoates / Q000494:pharmacology*; D005625:Frontal Lobe / Q000187:drug effects / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D010634:Phenobarbital / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012894:Sleep Stages / Q000187:drug effects*; D013997:Time Factors; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000241:Adenosine; D003651:Decanoates; D006993:Hypnotics and Sedatives; D010634:Phenobarbital; D010852:Picrotoxin; D011743:Pyrimidines; D014230:Triazoles; C000597394:3,4-dihydroxy-5-(6-((4-hydroxy-3-methoxybenzyl)amino)-9H-purin-9-yl)tetrahydrofuran-2-yl)methyl decanoate; C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine