Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the bind
Design and synthesis of novel derivatives of the muscarinic agonist tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (CDD-0304): effects of structural modifications on the bind
复制标题
毒蕈碱激动剂四(乙二醇)(3-甲氧基-1,2,5-噻二唑-4-基)[3-(1-甲基-1,2,5,6-四氢吡啶-)新型衍生物的设计和合成
DOI：
10.1021/jm0606995
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发表时间：
2006
影响因子：
7.3
通讯作者：
MesserJr,WilliamS
中科院分区：
文献类型：
--
作者：
Tejada,FrederickR;Nagy,PeterI;Xu,Min;Wu,Cindy;Katz,Tricia;Dorsey,Jason;Rieman,Melissa;Lawlor,Elizabeth;Warrier,Manya;MesserJr,WilliamS
作为设计和合成针对不同毒蕈碱受体亚型的高选择性毒蕈碱激动剂的持续努力的一部分，制备并表征了几种四（乙二醇）（3-甲氧基-1，2，5-噻二唑-4-基）[3-（1-甲基-1，2，5，6-四氢吡啶-3-基）-1，2，5-噻二唑-4-基]醚（1）类似物。合成了不同的类似物，其具有将1，2，5，6-四氢吡啶环与末端杂环（其为1，2，5-噻二唑或1，2，4-噻二唑环）分开的二-、三-、四-、五（乙二醇）和三（丙二醇）的亲水间隔基。嵌合受体和分子模拟研究也进行了，以确定如何与毒蕈碱受体的配体相互作用。研究表明，改变末端噻二唑的距离和甲氧基的位置可以增加对某些毒蕈碱受体亚型的结合亲和力（13 d的M2和1的M4），并增强对13 e和18 b的M4受体的功能效力。此外，化合物1表现出抗精神病活性，通过逆转阿扑吗啡诱导的感觉运动门控缺陷来评估，表明在治疗精神分裂症中的潜在效用。
As part of a continuing effort to design and synthesize highly selective muscarinic agonists for different muscarinic receptor subtypes, several tetra(ethylene glycol)(3-methoxy-1,2,5-thiadiazol-4-yl) [3-(1-methyl-1,2,5,6-tetrahydropyrid-3-yl)-1,2,5-thiadiazol-4-yl] ether (1) analogues were prepared and characterized. Different analogues were synthesized having hydrophilic spacers of di-, tri-, tetra-, penta(ethylene glycol) and tri(propylene glycol) separating the 1,2,5,6-tetrahydropyridine ring from the terminal heterocycle, which was either a 1,2,5-thiadiazole or 1,2,4-thiadiazole ring. Chimeric receptor and molecular modeling studies also were conducted to determine how the ligands interact with muscarinic receptors. The studies revealed that varying the distance of the terminal thiadiazole and the positioning of the methoxy group can increase binding affinity for certain muscarinic receptor subtypes (at M2for13dand M4for1) and enhance functional efficacy at M4receptors for13eand18b. Moreover, compound1exhibited antipsychotic activity as assessed by reversal of apomorphine-induced sensory motor gating deficits, suggesting potential utility in the treatment of schizophrenia.