2H-P2Y6受体对手的功能化原生
Paola Oliva1, Asmita Pramanik1, Young-Hwan Jung1
1Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
具有长链氨基酸修饰的新型P2Y6受体对抗剂显著增强了亲和力和选择性. 这些化合物,特别是类似物30 (MRS4940),显示出治疗炎症和退行性疾病的潜力.
科学领域:
- 药用化学 医学化学
- 药理学 药理学是指药理学的学科.
- 药物发现 药物发现 药物发现
背景情况:
- P2Y6受体 (P2Y6R) 是一种Gq合受体,涉及炎症和退行性疾病.
- 现有的对抗剂缺乏高 afinity,需要寻找新的治疗药物.
研究的目的:
- 研究作为P2Y6R抗体的3-nitro-2-(trifluoromethyl) -2H-chromene衍生物的结构-活性关系 (SAR).
- 识别具有增强亲和力和选择性的新型P2Y6R抗剂.
主要方法:
- 长链氨基功能化衍生物的合成和评估.
- 在人类P2Y6R转染细胞中测试UDP诱导的Ca2+调动.
- 确定IC50值和针对P2Y14R的选择性.
- 在45个受体位点进行非目标活性查.
主要成果:
- 长链氨基功能化烯显示显著增强的P2Y6R抗剂亲和力.
- 模拟物30 (MRS4940) 的IC50为162nM,其亲和力比原始化合物的亲和力大123倍.
- 化合物30显示P2Y6R对P2Y14R的选择性是132倍.
- 亲和度取决于链条长度,附着点和终端功能.
- 目标外查显示了一些类似物与生物氨基受体的相互作用.
结论:
- 长链氨基功能化衍生物是P2Y6R抗剂的一个有前途的类别.
- 模拟物30 (MRS4940) 显示出强大的和选择性的P2Y6R对抗性.
- 在炎症和癌症模型中进一步评估更强大的类似物是有必要的.
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