Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists.
Design, synthesis, and biological characterization of bivalent 1-methyl-1,2,5,6-tetrahydropyridyl-1,2,5-thiadiazole derivatives as selective muscarinic agonists.
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DOI：
10.1021/jm0102405
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发表时间：
2001-11
影响因子：
7.3
通讯作者：
W. G. Rajeswaran;Yang Cao;Xi-Ping Huang;M. E. Wroblewski;Tracy Colclough;Selina Lee;Fenghua Liu;Peter I. Nagy;James Ellis;Beth A. Levine;Karl H. Nocka;W. Messer
中科院分区：
文献类型：
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作者：
W. G. Rajeswaran;Yang Cao;Xi-Ping Huang;M. E. Wroblewski;Tracy Colclough;Selina Lee;Fenghua Liu;Peter I. Nagy;James Ellis;Beth A. Levine;Karl H. Nocka;W. Messer
选择性毒蕈碱激动剂可用于治疗神经系统疾病，如阿尔茨海默病、精神分裂症和慢性疼痛。已经开发了许多毒蕈碱激动剂，但大多数对给定受体亚型表现出最多有限的功能选择性，这可能是因为推定的结合位点内的高度序列同源性，其似乎隐藏在跨膜结构域内。合成在同一分子内基本上含有两个激动剂药效团的二价化合物，并测试其受体结合亲和力和毒蕈碱激动剂活性。通过烷氧基部分连接的一系列1，2，5，6-四氢吡啶的双-1，2，5-噻二唑衍生物表现出非常高的亲和力（K（i）< 1 nM）和强激动剂活性。活性程度取决于连接烷基的长度，其可以被聚（乙二醇）部分取代，从而改善水溶性、结合亲和力和激动剂效力。
Selective muscarinic agonists could be useful in the treatment of neurological disorders such as Alzheimer's disease, schizophrenia, and chronic pain. Many muscarinic agonists have been developed, yet most exhibit at best limited functional selectivity for a given receptor subtype perhaps because of the high degree of sequence homology within the putative binding site, which appears to be buried within the transmembrane domains. Bivalent compounds containing essentially two agonist pharmacophores within the same molecule were synthesized and tested for receptor binding affinity and muscarinic agonist activity. A series of bis-1,2,5-thiadiazole derivatives of 1,2,5,6-tetrahydropyridine linked by an alkyloxy moiety exhibited very high affinity (K(i) < 1 nM) and strong agonist activity. The degree of activity depended on the length of the linking alkyl group, which could be replaced by a poly(ethylene glycol) moiety, resulting in improved water solubility, binding affinity, and agonist potency.