Rafehi Muhammad, Malik Enas M, Neumann Alexander, Abdelrahman Aliaa, Hanck Theodor, Namasivayam Vigneshwaran, Müller Christa E, Baqi Younis
PharmaCenter Bonn, Pharmaceutical Institute, Pharmaceutical Chemistry I, Pharmaceutical Sciences Bonn (PSB), University of Bonn , An der Immenburg 4, D-53121 Bonn, Germany.
Department of Chemistry, Faculty of Science, Sultan Qaboos University , PO Box 36, Postal Code 123, Muscat, Oman.
J Med Chem. 2017 Apr 13;60(7):3020-3038. doi: 10.1021/acs.jmedchem.7b00030. Epub 2017 Mar 30.
P2Y is a G protein-coupled receptor activated by uridine-5'-triphosphate (UTP), which is widely expressed in the body, e.g., in intestine, heart, and brain. No selective P2Y receptor antagonist has been described so far. Therefore, we developed and optimized P2Y receptor antagonists based on an anthraquinone scaffold. Potency was assessed by a fluorescence-based assay measuring inhibition of UTP-induced intracellular calcium release in 1321N1 astrocytoma cells stably transfected with the human P2Y receptor. The most potent compound of the present series, sodium 1-amino-4-[4-(2,4-dimethylphenylthio)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate (PSB-16133, 61) exhibited an IC value of 233 nM, selectivity versus other P2Y receptor subtypes, and is thought to act as an allosteric antagonist. A receptor homology model was built and docking studies were performed to analyze ligand-receptor interactions. Compound 64 (PSB-1699, sodium 1-amino-4-[4-(3-pyridin-3-ylmethylthio)phenylamino]-9,10-dioxo-9,10-dihydroanthracene-2-sulfonate) represents the most selective P2Y receptor antagonist known to date. Compounds 61 and 64 are therefore anticipated to become useful tools for studying this scarcely investigated receptor.
P2Y是一种由尿苷-5'-三磷酸（UTP）激活的G蛋白偶联受体，在体内广泛表达，例如在肠道、心脏和大脑中。迄今为止，尚未有选择性P2Y受体拮抗剂的报道。因此，我们基于蒽醌骨架开发并优化了P2Y受体拮抗剂。通过基于荧光的测定法评估效力，该测定法测量在稳定转染了人P2Y受体的1321N1星形细胞瘤细胞中UTP诱导的细胞内钙释放的抑制情况。本系列中最有效的化合物1-氨基-4-[4-(2,4-二甲基苯硫基)苯基氨基]-9,10-二氧代-9,10-二氢蒽-2-磺酸钠（PSB-16133，61）的IC值为233 nM，对其他P2Y受体亚型具有选择性，被认为是一种变构拮抗剂。构建了受体同源模型并进行对接研究以分析配体-受体相互作用。化合物64（PSB-1699，1-氨基-4-[4-(3-吡啶-3-基甲基硫基)苯基氨基]-9,10-二氧代-9,10-二氢蒽-2-磺酸钠）是迄今为止已知的最具选择性的P2Y受体拮抗剂。因此，预计化合物61和64将成为研究这种研究较少的受体的有用工具。
