| Autor: |
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 |
| Zdroj: |
Journal of Medicinal Chemistry; January 2019, Vol. 62 Issue: 1 p159-173, 15p |
| Abstrakt: |
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 Xenopusooctyes by a two-electrode voltage clamp. The structure–activity relationship analysis identified the compound 3eaas 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 GABAAreceptors. Compound 3eashowed 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 3eadose-dependently (0.1–1 mg/kg, i.p.) reversed the prepulse inhibition deficit induced by MK-801 in the mouse schizophrenia model. |
| Databáze: |
Supplemental Index |
| Externí odkaz: |
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