Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Cells. 2024 Aug 16;13(16):1366. doi: 10.3390/cells13161366.
The P2Y receptor (P2YR), a G-coupled receptor, is a potential drug discovery target for various inflammatory and degenerative conditions. Antagonists have been shown to attenuate colitis, acute lung injury, etc. In the search for competitive antagonists, we have investigated the SAR of 3-nitro-2-(trifluoromethyl)-2-chromene derivatives, although high affinity is lacking. We now reveal that long-chain amino-functionalized congeners display greatly enhanced affinity in the antagonism of UDP-induced Ca mobilization in (h) P2YR-transfected 1321N1 astrocytoma cells. A 6-(Boc-amino--heptylethynyl) analogue (MRS4940) had an IC of 162 nM, which was a 123-fold greater affinity than the corresponding unprotected primary alkylamine, 107-fold greater than the corresponding pivaloyl derivative , and 132-fold selective compared to the P2YR. However, similar Boc-amino chains attached at the 8-position produced weak µM affinity. Thus, the P2YR affinity depended on the chain length, attachment point, and terminal functionality. Off-target activities, at 45 sites, were tested for acylamino derivatives , , , , , and , which showed multiple interactions, particularly at the biogenic amine receptors. The more potent analogues may be suitable for evaluation in inflammation and cancer models, which will be performed in future studies.
P2Y 受体（P2YR）是一种 G 蛋白偶联受体，是各种炎症和退行性疾病的潜在药物发现靶点。已证明拮抗剂可减轻结肠炎、急性肺损伤等。在寻找竞争性拮抗剂的过程中，我们研究了 3-硝基-2-（三氟甲基）-2-色烯衍生物的 SAR，尽管亲和力不高。我们现在揭示，长链氨基官能化同系物在拮抗 UDP 诱导的 Ca 动员方面显示出大大增强的亲和力在转染的 1321N1 星形细胞瘤细胞中的 (h) P2YR。6-（Boc-氨基--庚基乙炔基）类似物 （MRS4940）的 IC 为 162 nM，比相应的未保护的伯烷基胺高 123 倍，比相应的特戊酰衍生物高 107 倍，与 P2YR 相比高 132 倍。然而，在 8 位连接类似的 Boc-氨基链产生了弱的 µM 亲和力。因此，P2YR 的亲和力取决于链长、连接点和末端官能团。在 45 个位点测试了酰氨基衍生物 、 、 、 、 、 ，它们显示出多种相互作用，特别是在生物胺受体上。更有效的类似物可能适合在炎症和癌症模型中进行评估，这将在未来的研究中进行。
