Zhuo Tongyou, Zhou Shengxue, Zhang Wei, Lambertucci Catia, Volpini Rosaria
School of Food Technology, Jilin Agricultural Science and Technology College, Jilin City, Jilin, China (mainland).
College of Chinese Medicine, Jilin Agricultural Science and Technology College, Jilin City, Jilin, China (mainland).
Med Sci Monit. 2017 Feb 22;23:953-959. doi: 10.12659/msm.902048.
GPR17 is believed to be a novel target for the development of new therapeutic approaches to human stroke and multiple sclerosis. Hence, the selection of GPR17 ligands may be a potent way to reduce the progression of ischemic damage. New potential ligands for GPR17, mono-, di-, and triphosphate adenosine nucleotides substituted at N6-position with a methyl and a cyclopentyl group were synthesized. The ability of new ligands to bind GPR17 was evaluated using frontal affinity chromatography-mass spectrometry (FAC-MS) method. Cangrelor, MRS2179, and uridine diphosphate were selected as the reference compounds. The new triphosphate derivatives 9 and 10 were considered as the new GPR17 ligands. The compound 10 was eluted with breakthrough time (bt) between cangrelor and MRS 2179 (compound 10, bt=12.25; cangrelor, bt=24.55, and MRS 2179, bt=7.10), while the breakthrough volume of compound 9 was similar to that of MRS 2179 (compound 9, bt=7.53 and MRS 2179, bt=7.10). N6-cyclopentyATP 10 is medium-high affinity ligand of GPR17, while the corresponding N6-methyl derivative 9 is a medium affinity ligand similar to MRS 2179. Hence, the new N6-cyclopentylATP 10 might be a good candidate for the pharmacological characterization of GPR17.
GPR17被认为是开发人类中风和多发性硬化症新治疗方法的一个新靶点。因此，选择GPR17配体可能是减少缺血性损伤进展的有效方法。合成了在N6位被甲基和环戊基取代的GPR17新潜在配体，即单磷酸、二磷酸和三磷酸腺苷核苷酸。使用前沿亲和色谱-质谱（FAC-MS）方法评估新配体与GPR17结合的能力。选择坎格雷洛、MRS2179和尿苷二磷酸作为参考化合物。新的三磷酸衍生物9和10被视为新的GPR17配体。化合物10的洗脱突破时间（bt）介于坎格雷洛和MRS 2179之间（化合物10，bt = 12.25；坎格雷洛，bt = 24.55，MRS 2179，bt = 7.10），而化合物9的突破体积与MRS 2179相似（化合物9，bt = 7.53，MRS 2179，bt = 7.10）。N6-环戊基三磷酸腺苷10是GPR17的中高亲和力配体，而相应的N6-甲基衍生物9是与MRS 2179相似的中等亲和力配体。因此，新的N6-环戊基三磷酸腺苷10可能是GPR17药理学特性研究的良好候选物。
