39736-35-1Relevant articles and documents
Design and Synthesis of Novel Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors with the Ability to Rescue Auditory Gating Deficit in Mice
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
, p. 159 - 173 (2019)
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.
