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Design and Synthesis of Novel Positive Allosteric Modulators of α7 Nicotinic Acetylcholine Receptors with the Ability To Rescue Auditory Gating Deficit in Mice

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journal contribution
posted on 2018-03-28, 00:00 authored by Yuanheng Li, Lilan Sun, Taoyi Yang, Wenxuan Jiao, Jingshu Tang, Xiaomin Huang, Zongze Huang, Ying Meng, Laichun Luo, Xintong Wang, Xiling Bian, Fang Zhang, KeWei Wang, Qi Sun
A series of novel thiazolo­[4,5-d]­pyrimidin-7­(6H)-ones (3aa3eq) 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.