Olsson R A, Kusachi S, Thompson R D, Ukena D, Padgett W, Daly J W
J Med Chem. 1986 Sep;29(9):1683-9. doi: 10.1021/jm00159a020.
The coronary vasoactivity of N-ethyl-1'-deoxy-1'-(6-amino-9H-purin-9-yl)-beta-D-ribofuranuronamide (NECA, 1) is over 2 orders of magnitude greater than that of adenosine, and the vasoactivity of certain N6-substituted adenosines is as much as 1 order of magnitude greater. Such results suggest that a combination of appropriate modifications at N6 and C-5' might additively augment the agonist potency of adenosine. At low temperatures 1-deoxy-1-(6-chloro-9H-purin-9-yl)-2',3'-O-isopropylidene- beta-D-ribofuranosyl chloride (5), obtained in three steps from inosine, reacts with amines to yield uronamides. The subsequent reaction of such uronamides with amines at elevated temperatures displaces the purine 6-chloro group to yield, after deblocking, N-alkyl(or aryl)-N6-alk(ar)yl-adenosine-5'-uronamides. At the coronary artery A2 receptor the potency of N6-modified analogues of 1 is similar to that of the N6-substituted adenosine, rather than equal to or greater than 1. As agonists in the A2 receptor-mediated stimulation of adenylate cyclase in plasma membranes of PC12 pheochromocytoma cells or human platelets, N6-substituted analogues of 1 are intermediate between the high potency of 1 and the lower potency of the N6-substituted adenosines. At the A1 receptor of rat brain the potency of an N6-substituted analogue of 1 is often greater than that of the corresponding N6-substituted adenosine. At all four receptors, replacing the ethyl group of N-ethyl-N6-3-pentyladenosine-5'-uronamide by larger alkyl groups reduces potency; amides of secondary amines are inactive or have only marginal activity. Analogues of 1 containing a chiral center in the N6 substituent retain the stereoselectivity characteristic of each of the four receptors. Thus, at either A1 or A2 adenosine receptors, adenosine analogues interact with both the N6 and the C-5' receptor regions. However, the effects of N6 and C-5' modifications on potency are less than additive, evidence that the interaction of a substituent with its receptor region influences the interaction of other substituents with their respective receptor regions.
N-乙基-1'-脱氧-1'-(6-氨基-9H-嘌呤-9-基)-β-D-呋喃核糖脲苷（NECA，1）的冠脉血管活性比腺苷高2个数量级以上，某些N6-取代腺苷的血管活性也比腺苷高1个数量级之多。这些结果表明，在N6和C-5'处进行适当修饰的组合可能会累加增强腺苷的激动剂效力。在低温下，由肌苷经三步反应制得的1-脱氧-1-(6-氯-9H-嘌呤-9-基)-2',3'-O-异丙叉基-β-D-呋喃核糖基氯（5）与胺反应生成脲苷酰胺。这些脲苷酰胺随后在高温下与胺反应，取代嘌呤6-氯基团，经脱保护后得到N-烷基（或芳基）-N6-烷（芳）基-腺苷-5'-脲苷酰胺。在冠状动脉A2受体处，1的N6-修饰类似物的效力与N6-取代腺苷的效力相似，而非等于或大于1。作为A2受体介导的PC12嗜铬细胞瘤细胞或人血小板质膜中腺苷酸环化酶刺激的激动剂，1的N6-取代类似物的效力介于1的高效力和N6-取代腺苷的低效力之间。在大鼠脑的A1受体处，1的N6-取代类似物的效力通常大于相应的N6-取代腺苷。在所有这四种受体处，用更大的烷基取代N-乙基-N6-3-戊基腺苷-5'-脲苷酰胺的乙基会降低效力；仲胺的酰胺无活性或只有微弱活性。在N6取代基中含有手性中心的1的类似物保留了这四种受体各自的立体选择性特征。因此，在A1或A2腺苷受体处，腺苷类似物与N6和C-5'受体区域都相互作用。然而，N6和C-5'修饰对效力的影响小于累加效应，这证明一个取代基与其受体区域的相互作用会影响其他取代基与其各自受体区域的相互作用。
