Journal of Medicinal Chemistry p. 159 - 173 (2019)
Update date:2022-08-15
Topics:
Li, Yuanheng
Sun, Lilan
Yang, Taoyi
Jiao, Wenxuan
Tang, Jingshu
Huang, Xiaomin
Huang, Zongze
Meng, Ying
Luo, Laichun
Wang, Xintong
Bian, Xiling
Zhang, Fang
Wang, Kewei
Sun, Qi
A series of novel thiazolo[4,5-d]pyrimidin-7(6H)-ones (3aa-3eq) were designed, synthesized, and evaluated as the type I positive allosteric modulators of human α7 nAChR expressed in Xenopus ooctyes by a two-electrode voltage clamp. The structure-activity relationship analysis identified the compound 3ea as a potent and efficacious PAM with the maximum activation effect of the α7 current of over 1633% in the presence of acetylcholine (100 μM) and an EC50 = 1.26 μM. It is highly specific to α7 nAChR over other subtypes of nAChR, 5-HT3A, NMDA, and GABAA receptors. Compound 3ea showed an elimination half-life of 10.8 ± 1.5 h for 3 mg/kg, i.v., and 7.4 ± 1.1 h for 60 mg/kg, i.g. in rat. It also exhibited sufficient blood-brain barrier penetration with no significant effect on hERG channel. Most importantly, compound 3ea dose-dependently (0.1-1 mg/kg, i.p.) reversed the prepulse inhibition deficit induced by MK-801 in the mouse schizophrenia model.
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