Francis J E, Webb R L, Ghai G R, Hutchison A J, Moskal M A, deJesus R, Yokoyama R, Rovinski S L, Contardo N, Dotson R
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
J Med Chem. 1991 Aug;34(8):2570-9. doi: 10.1021/jm00112a035.
A wide variety of 2-substituted aminoadenosines were prepared for comparison with the moderately A2 receptor selective adenosine agonist 2-anilinoadenosine (CV-1808). High selectivity combined with significant affinity at the A2 receptor in rat membranes was observed for those amines bearing a two-carbon chain to which was attached an aryl, heteroaryl, or alicyclic moiety. 2-(2-Phenethylamino)adenosine (3d), a 14-fold A2 selective compound, was modified by introduction of a variety of substituents in the benzene ring and the side chain. Some of these changes led to improved A2 affinity and increased selectivity. Replacement of the phenyl moiety by cyclohexenyl produced a 210-fold selective agonist 3ag (CGS 22989) whereas the cyclohexanyl analogue 3af (CGS 22492) was 530-fold selective at the A2 site. These compounds showed hypotensive activity in rat models over a range of doses without the bradycardia observed with less selective agonists.
制备了多种2-取代氨基腺苷，用于与中度A2受体选择性腺苷激动剂2-苯胺基腺苷（CV-1808）进行比较。对于那些带有连接芳基、杂芳基或脂环族部分的二碳链的胺类，在大鼠膜中观察到其在A2受体上具有高选择性并结合显著亲和力。2-(2-苯乙氨基)腺苷（3d）是一种具有14倍A2选择性的化合物，通过在苯环和侧链中引入多种取代基对其进行修饰。其中一些变化导致A2亲和力提高和选择性增加。用环己烯基取代苯基部分产生了一种具有210倍选择性的激动剂3ag（CGS 22989），而环己基类似物3af（CGS 22492）在A2位点具有530倍选择性。这些化合物在大鼠模型中在一定剂量范围内显示出降压活性，而没有观察到选择性较低的激动剂所引起的心动过缓。
