将 Pro-Leu-Gly-NH2 肽模拟物型多巴胺 D2 受体正变构调节剂转化为负变构调节剂。
Transformation of Pro-Leu-Gly-NH2 peptidomimetic positive allosteric modulators of the dopamine D2 receptor into negative modulators.
机构信息
Department of Medicinal Chemistry, University of Minnesota, 308 Harvard Street SE, Minneapolis, Minnesota 55455, United States.
出版信息
ACS Chem Neurosci. 2012 Apr 18;3(4):274-84. doi: 10.1021/cn200096u. Epub 2012 Jan 13.
Abstract
The synthesis of dimethyl derivatives of 5.6.5 spiro bicyclic lactam Pro-Leu-Gly-NH(2) peptidomimetics was carried out to test the hypothesis that by placing methyl groups on the β-methylene carbon of the thiazolidine ring steric bulk would be introduced into the topological space that the β-methylene carbon is believed to occupy in the negative allosteric modulators of the dopamine D(2) receptor. With such a modification, a positive allosteric modulator would be converted into a negative allosteric modulator. This hypothesis was shown to be correct as 3a and 4a where found to be negative allosteric modulators, whereas their unmethylated derivatives were positive allosteric modulators of the dopamine D(2) receptor.
摘要
我们合成了 5.6.5 螺环二环内酰胺 Pro-Leu-Gly-NH(2) 肽类似物的二甲衍生物，以验证以下假设：通过在噻唑烷环的β-亚甲基碳原子上引入甲基，将空间位阻引入到β-亚甲基碳原子被认为在多巴胺 D(2) 受体的负变构调节剂中占据的拓扑空间中。通过这种修饰，正变构调节剂将转化为负变构调节剂。该假设被证明是正确的，因为 3a 和 4a 被发现是负变构调节剂，而它们的未甲基化衍生物是多巴胺 D(2) 受体的正变构调节剂。
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