Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A.
Synthesis and pharmacological characterization of new neuronal nicotinic acetylcholine receptor ligands derived from Sazetidine-A.
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DOI：
10.1016/j.bmcl.2014.04.036
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发表时间：
2014-07
影响因子：
2.7
通讯作者：
Y. Liu;M. Paige;Thao T. Olson;Nour Al-muhtasib;Teresa Xie;Shujie Hou;M. P. White;Antoinette Cordova;Jessica L Guo;K. Kellar;Yingxian Xiao;Milton L. Brown
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文献类型：
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作者：
Y. Liu;M. Paige;Thao T. Olson;Nour Al-muhtasib;Teresa Xie;Shujie Hou;M. P. White;Antoinette Cordova;Jessica L Guo;K. Kellar;Yingxian Xiao;Milton L. Brown
合成了两个沙西丁-A类似物的对映体以及其他几个新的生物立体类似物。测定了它们在三种主要nAChRs亚型和选择性图谱上的结合亲和力。尽管许多沙氮替丁-A类似物的(S)对映体具有很高的结合亲和力和良好的亚型选择性，但(S)对映体并不是普遍优于(R)对映体。化合物11的乙炔基通过点击化学被其生物异构体-三氮唑取代，与α4β2亚型(Ki=91.3 nm)具有较高的结合亲和力，并且对α4β2亚型的选择性高于α3β4亚型和沙西替丁-A。叠氮化合物15是一种潜在的光亲和标记，显示出改进的高选择性和与沙替替丁-A相似的结合特性。联芳基类似物17的亲和力远低于沙滋丁-A，这表明‘长尾’侧链对α4β2nAChR结合的重要性。
The enantiomers of two analogs of Sazetidine-A as well as several other novel biosteric analogues were synthesized. Their binding affinities at three major nAChRs subtypes and selectivity profiles were determined. Though many (S)-enantiomers of Sazetidine-A analogs have high binding affinities and good subtype selectivities, it is not a general rule that (S)-enantiomers are better than their (R) counterparts. Compound11, of which the ethynyl group was replaced by its’ bioisostere—the triazole via click chemistry, showed a high binding affinity to α4β2 subtype (Ki= 1.3 nM) and better selectivity to the α4β2 subtype over α3β4 subtype with that of Sazetidine-A. The azide compound15, a potential photoaffinity label, showed improved high selectivity and similar binding property profile with that of Sazetidine-A. The biaryl analog17exhibited a much lower affinity as compared to Sazetidine-A indicating the importance of a ‘long tail’ side chain for α4β2 nAChR binding.