Gao Zhan-Guo, Blaustein Joshua B, Gross Ariel S, Melman Neli, Jacobson Kenneth A
Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Room B1A-19, Building 8A, Bethesda, MD 20892, USA.
Biochem Pharmacol. 2003 May 15;65(10):1675-84. doi: 10.1016/s0006-2952(03)00153-9.
The activation of the human A(3) adenosine receptor (AR) by a wide range of N(6)-substituted adenosine derivatives was studied in intact CHO cells stably expressing this receptor. Selectivity of binding at rat and human ARs was also determined. Among N(6)-alkyl substitutions, small N(6)-alkyl groups were associated with selectivity for human A(3)ARs vs. rat A(3)ARs, and multiple points of branching were associated with decreased hA(3)AR efficacy. N(6)-Cycloalkyl-substituted adenosines were full (</=5 carbons) or partial (>/=6 carbons) hA(3)AR agonists. N(6)-(endo-Norbornyl)adenosine 13 was the most selective for both rat and human A(1)ARs. Numerous N(6)-arylmethyl analogues, including substituted benzyl, tended to be more potent in binding to A(1) and A(3) vs. A(2A)ARs (with variable degrees of partial to full A(3)AR agonisms). A chloro substituent decreased the efficacy depending on its position on the benzyl ring. The A(3)AR affinity and efficacy of N(6)-arylethyl adenosines depended highly on stereochemistry, steric bulk, and ring constraints. Stereoselectivity of binding was demonstrated for N(6)-(R-1-phenylethyl)adenosine vs. N(6)-(S-1-phenylethyl)adenosine, as well as for the N(6)-(1-phenyl-2-pentyl)adenosine, at the rat, but not human A(3)AR. Interestingly, DPMA, a potent agonist for the A(2A)AR (K(i)=4nM), was demonstrated to be a moderately potent antagonist for the human A(3)AR (K(i)=106nM). N(6)-[(1S,2R)-2-Phenyl-1-cyclopropyl]adenosine 48 was 1100-fold more potent in binding to human (K(i)=0.63nM) than rat A(3)ARs. Dual acting A(1)/A(3) agonists (N(6)-3-chlorobenzyl- 29, N(6)-(S-1-phenylethyl)- 39, and 2-chloro-N(6)-(R-phenylisopropyl)adenosine 53) might be useful for cardioprotection.
在稳定表达人 A(3) 腺苷受体（AR）的完整 CHO 细胞中，研究了多种 N(6)-取代腺苷衍生物对人 A(3) 腺苷受体的激活作用。还测定了在大鼠和人 AR 上结合的选择性。在 N(6)-烷基取代中，小的 N(6)-烷基与人 A(3)AR 相对于大鼠 A(3)AR 的选择性相关，而多个分支点与 hA(3)AR 效力降低相关。N(6)-环烷基取代的腺苷是完全（≤5 个碳）或部分（≥6 个碳）的 hA(3)AR 激动剂。N(6)-(内-降冰片基)腺苷 13 对大鼠和人 A(1)AR 都是最具选择性的。许多 N(6)-芳基甲基类似物，包括取代苄基，与 A(2A)AR 相比，往往与 A(1)和 A(3)的结合更强（具有不同程度的部分至完全 A(3)AR 激动作用）。氯取代基根据其在苄基环上的位置降低效力。N(6)-芳基乙基腺苷的 A(3)AR 亲和力和效力高度依赖于立体化学、空间体积和环限制。N(6)-(R-1-苯乙基)腺苷与 N(6)-(S-1-苯乙基)腺苷以及 N(6)-(1-苯基-2-戊基)腺苷在大鼠 A(3)AR 上表现出结合的立体选择性，但在人 A(3)AR 上未表现出。有趣的是，DPMA 是 A(2A)AR 的强效激动剂（K(i)=4nM），被证明是人类 A(3)AR 的中度强效拮抗剂（K(i)=106nM）。N(6)-[(1S,2R)-2-苯基-1-环丙基]腺苷 48 与人 A(3)AR（K(i)=0.63nM）结合的效力比大鼠 A(3)AR 高 1100 倍。双效 A(1)/A(3)激动剂（N(6)-3-氯苄基-29、N(6)-(S-1-苯乙基)-39 和 2-氯-N(6)-(R-苯基异丙基)腺苷 53）可能对心脏保护有用。
