van Muijlwijk-Koezen J E, Timmerman H, Link R, van der Goot H, IJzerman A P
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Department of Pharmacochemistry, Vrije Universiteit, De Boelelaan 1083, 1081 HV Amsterdam, The Netherlands.
J Med Chem. 1998 Oct 8;41(21):3987-93. doi: 10.1021/jm980036q.
A series of 3-(2-pyridinyl)isoquinoline derivatives was synthesized as potential antagonists for the human adenosine A3 receptor by substitution of the 1-position. The compounds were obtained by various synthetic routes from 1-amino-3-(2-pyridinyl)isoquinoline. The affinity was determined in radioligand binding assays for rat brain A1 and A2A receptors and for the cloned human A3 receptor. A structure-activity relationship analysis indicated that a phenyl group when coupled by a spacer allowing conjugation on position 1 of the isoquinoline ring increased the adenosine A3 receptor affinity. In contrast, such a phenyl group directly bound to position 1 of the isoquinoline ring decreased affinity. Since the combination of a phenyl group together with a spacer raised adenosine A3 receptor affinity, various spacers were investigated. VUF8501 (N-[3-(2-pyridinyl)isoquinolin-1-yl]benzamidine (15) showed an affinity at the human adenosine A3 receptor of 740 nM. Substituent effects on the phenyl group were investigated by in vitro evaluation of a series of substituted benzamidines. Electron-donating groups at the para position of the benzamidine ring increased adenosine A3 receptor affinity. These investigations led to VUF8505 (4-methoxy-N-[3-(2-pyridinyl)isoquinolin-1-yl]benzamidine(22)), which is a moderately potent and selective ligand for the human adenosine A3 receptor with an affinity of 310 nM in our test system having negligible affinity for rat A1 and A2A receptors.
通过对1位进行取代，合成了一系列3-(2-吡啶基)异喹啉衍生物，作为人腺苷A3受体的潜在拮抗剂。这些化合物通过多种合成路线从1-氨基-3-(2-吡啶基)异喹啉制得。通过放射性配体结合试验测定了这些化合物对大鼠脑A1和A2A受体以及克隆的人A3受体的亲和力。结构-活性关系分析表明，当苯基通过一个间隔基团连接，使得能够在异喹啉环的1位发生共轭时，腺苷A3受体亲和力增加。相反，这样一个直接连接到异喹啉环1位的苯基会降低亲和力。由于苯基与间隔基团的组合提高了腺苷A3受体亲和力，因此对各种间隔基团进行了研究。VUF8501（N-[3-(2-吡啶基)异喹啉-1-基]苯甲脒(15)）在人腺苷A3受体上的亲和力为740 nM。通过对一系列取代苯甲脒的体外评估研究了苯基上的取代基效应。苯甲脒环对位的供电子基团增加了腺苷A3受体亲和力。这些研究得到了VUF8505（4-甲氧基-N-[3-(2-吡啶基)异喹啉-1-基]苯甲脒(22)），它是一种对人腺苷A3受体具有中等效力和选择性的配体，在我们的测试系统中亲和力为310 nM，对大鼠A1和A2A受体的亲和力可忽略不计。
