Hutchison A J, Williams M, de Jesus R, Yokoyama R, Oei H H, Ghai G R, Webb R L, Zoganas H C, Stone G A, Jarvis M F
Research Department, CIBA-GEIGY Corporation, Summit, New Jersey 07901.
J Med Chem. 1990 Jul;33(7):1919-24. doi: 10.1021/jm00169a015.
The synthesis and receptor-binding profiles at adenosine receptor subtypes for a series of 2-(arylalkylamino)-adenosin-5'-uronamides is described. Halogenated 2-phenethylamino analogues such as 3e show greater than 200-fold selectivity for the A2 receptor subtype on the basis of rat brain receptor binding. The general structure-activity relationship of this series of compounds is discussed both in terms of potency at A2 receptors as well as receptor subtype selectivity. It is possible to introduce a hydrophilic carboxyalkyl substituent to this series such as in CGS 21680A (3h) and still retain good potency and selectivity for A2 receptors. In addition, functional data in a perfused working rat heart model shows that these compounds possess full agonist properties at A2 receptors with 3h having a greater than 1500-fold separation between A2 (coronary vasodilatory) and A1 (negative chronotropic) receptor mediated events.
本文描述了一系列2-(芳基烷基氨基)-腺苷-5'-脲酰胺在腺苷受体亚型上的合成及受体结合情况。基于大鼠脑受体结合实验，卤代2-苯乙氨基类似物如3e对A2受体亚型显示出大于200倍的选择性。从A2受体的活性以及受体亚型选择性两方面讨论了该系列化合物的一般构效关系。向该系列化合物中引入亲水性羧基烷基取代基是可行的，如在CGS 21680A（3h）中，且仍能保持对A2受体良好的活性和选择性。此外，在灌注工作大鼠心脏模型中的功能数据表明，这些化合物在A2受体上具有完全激动剂特性，3h在A2（冠状动脉舒张）和A1（负性变时）受体介导的事件之间具有大于1500倍的分离度。
