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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01492 Yuanheng Li 1 , Lilan Sun 2 , Taoyi Yang 3 , Wenxuan Jiao 1 , Jingshu Tang 3 , Xiaomin Huang 3 , Zongze Huang 1 , Ying Meng 1 , Laichun Luo 1 , Xintong Wang 3 , Xiling Bian 3 , Fang Zhang 2 , KeWei Wang 1, 2, 3 , Qi Sun 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2018-03-28 00:00:00 , DOI: 10.1021/acs.jmedchem.7b01492 Yuanheng Li 1 , Lilan Sun 2 , Taoyi Yang 3 , Wenxuan Jiao 1 , Jingshu Tang 3 , Xiaomin Huang 3 , Zongze Huang 1 , Ying Meng 1 , Laichun Luo 1 , Xintong Wang 3 , Xiling Bian 3 , Fang Zhang 2 , KeWei Wang 1, 2, 3 , Qi Sun 1
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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.
中文翻译：
能够挽救小鼠听觉门控缺陷的新型α7烟碱乙酰胆碱受体正构构调节剂的设计与合成
设计，合成了一系列新颖的噻唑并[4,5- d ]嘧啶7（6 H）-ones（3aa - 3eq），并将其作为在非洲爪蟾中表达的人α7nAChR的I型正变构调节剂。两电极电压钳。结构-活性关系分析表明，在乙酰胆碱（100μM）和EC 50 = 1.26μM存在的情况下，化合物3ea是有效的PAM，α7电流的最大活化作用超过1633％。它对α7nAChR的特异性高于nAChR，5-HT 3A，NMDA和GABA A受体的其他亚型。化合物3ea在ig中显示3 mg / kg静脉注射的消除半衰期为10.8±1.5 h，60 mg / kg静脉注射的消除半衰期为7.4±1.1 h。它也表现出足够的血脑屏障渗透性，对hERG通道无明显影响。最重要的是，化合物3ea剂量依赖性（0.1-1 mg / kg，ip）可以逆转MK-801在小鼠精神分裂症模型中引起的前脉冲抑制功能障碍。
更新日期：2018-03-28
中文翻译：
能够挽救小鼠听觉门控缺陷的新型α7烟碱乙酰胆碱受体正构构调节剂的设计与合成
设计，合成了一系列新颖的噻唑并[4,5- d ]嘧啶7（6 H）-ones（3aa - 3eq），并将其作为在非洲爪蟾中表达的人α7nAChR的I型正变构调节剂。两电极电压钳。结构-活性关系分析表明，在乙酰胆碱（100μM）和EC 50 = 1.26μM存在的情况下，化合物3ea是有效的PAM，α7电流的最大活化作用超过1633％。它对α7nAChR的特异性高于nAChR，5-HT 3A，NMDA和GABA A受体的其他亚型。化合物3ea在ig中显示3 mg / kg静脉注射的消除半衰期为10.8±1.5 h，60 mg / kg静脉注射的消除半衰期为7.4±1.1 h。它也表现出足够的血脑屏障渗透性，对hERG通道无明显影响。最重要的是，化合物3ea剂量依赖性（0.1-1 mg / kg，ip）可以逆转MK-801在小鼠精神分裂症模型中引起的前脉冲抑制功能障碍。
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