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腺苷受体前药：强效A1选择性激动剂衍生物的合成与生物活性

Adenosine receptor prodrugs: synthesis and biological activity of derivatives of potent, A1-selective agonists.

作者信息

Maillard M C, Nikodijević O, LaNoue K F, Berkich D, Ji X D, Bartus R, Jacobson K A

机构信息

Hershey Medical Center, Pennsylvania State University, Hershey.

出版信息

J Pharm Sci. 1994 Jan;83(1):46-53. doi: 10.1002/jps.2600830112.

DOI:10.1002/jps.2600830112
PMID:8138909
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC3459066/
Abstract

5'-Ester derivatives of the potent adenosine agonists N6-[4-[[[[4-[[[(2-acetylaminoethyl)amino]carbonyl]methyl] anilino]carbonyl]methyl]phenyl]adenosine (N-AcADAC; 1) and N6-cyclopentyladenosine (CPA; 2) were prepared as prodrugs. Both alkyl esters or carbonates (designed to enter the brain by virtue of increased lipophilicity) and 1,4-dihydro-1-methyl-3-[(pyridinylcarbonyl)oxy]esters designed to concentrate in the brain by virtue of a redox delivery system were synthesized. In the 5'-blocked form, the adenosine agonists displayed highly diminished affinity for rat brain A1-adenosine receptors in binding assays. The dihydropyridine prodrug 29 was active in an assay of locomotor depression in mice, in which adenosine agonists are highly depressant. The behavior depression was not reversible by peripheral administration of a non-central nervous system active adenosine antagonist. In an assay of the peripheral action of adenosine (i.e., the inhibition of lipolysis in rats), the parent compounds were highly potent and the dihydropyridine prodrug was much less potent.

摘要

强效腺苷激动剂N6-[4-[[[[4-[[[(2-乙酰氨基乙基)氨基]羰基]甲基]苯胺基]羰基]甲基]苯基]腺苷（N-乙酰基-ADA-C；1）和N6-环戊基腺苷（CPA；2）的5'-酯衍生物被制备为前药。合成了烷基酯或碳酸酯（旨在通过增加亲脂性进入大脑）以及旨在通过氧化还原递送系统在大脑中富集的1,4-二氢-1-甲基-3-[(吡啶基羰基)氧基]酯。在5'-封闭形式下，腺苷激动剂在结合试验中对大鼠脑A1-腺苷受体的亲和力显著降低。二氢吡啶前药29在小鼠运动抑制试验中具有活性，在该试验中腺苷激动剂具有高度抑制作用。外周给予非中枢神经系统活性的腺苷拮抗剂不能逆转行为抑制。在腺苷外周作用试验（即抑制大鼠脂肪分解）中，母体化合物具有高效力，而二氢吡啶前药的效力则低得多。

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