SYNTHESIS AND BIOLOGICAL PROPERTIES OF 2-FLUORONOREPINEPHRINES, 5-FLUORONOREPINEPHRINES, AND 6-FLUORONOREPINEPHRINES
SYNTHESIS AND BIOLOGICAL PROPERTIES OF 2-FLUORONOREPINEPHRINES, 5-FLUORONOREPINEPHRINES, AND 6-FLUORONOREPINEPHRINES
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DOI：
10.1021/jm00198a012
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发表时间：
1979-01-01
影响因子：
7.3
通讯作者：
CREVELING, CR
中科院分区：
文献类型：
--
作者：
KIRK, KL;CANTACUZENE, D;CREVELING, CR
通过光化学分解相应的重氮氟硼酸盐制备了2-氟-、5-氟-和6-氟二甲氧基苯甲醛。醛转化为氰醇三甲基甲硅烷基醚，其又被还原为二甲氧基苯乙醇胺。BBr 3去甲基化得到外消旋环氟化去甲肾上腺素。另一种使用二苄氧基氟醛的途径也用于制备6-氟罗哌卡因。氟取代基显着增加这些类似物的酚酸。在外周和中枢肾上腺素能反应系统中由氟取代基赋予去甲肾上腺素的生物学性质清楚地证明2-氟肾上腺素是几乎纯的β-肾上腺素。肾上腺素能激动剂，而6-氟诺啡肽是α-肾上腺素能激动剂。肾上腺素能激动剂5-氟罗哌酮保留了β-和α-肾上腺素能激动剂性质。用特异性放射性标记的配体进行的受体结合研究表明，氟取代基位点赋予的特异性是由这些类似物对α-受体的亲和力的变化引起的。和β-肾上腺素能受体在豚鼠心房、主动脉条、回肠和大鼠大脑皮质切片上进行了试验。
2-Fluoro-, 5-fluoro- and 6-fluorodimethoxybenzaldehydes were prepared by photochemical decomposition of the corresponding diazonium fluoroborates. The aldehydes were converted to the cyanohydrin trimethylsilyl ethers, which, in turn, were reduced to the dimethoxyphenethanolamines. BBr3 demethylation afforded the racemic ring-fluorinated norepinephrines. An alternate route, using the dibenzyloxyfluoroaldehyde, was also used to prepare 6-fluoronorepinephrine. The fluorine substituent markedly increases the phenolic acidities of these analogs. The biological properties conferred upon norepinephrine by the fluorine substituents in peripheral and central adrenergically responsive systems clearly demonstrate that 2-fluoronorepinephrine is a nearly pure .beta.-adrenergic agonist, while 6-fluoronorepinephrine is an .alpha.-adrenergic agonist. 5-Fluoronorepinephrine retains both .beta.- and .alpha.-adrenergic agonist properties. Receptor-binding studies with specific radiolabeled ligands indicate that the specificity conferred by the site of fluorine substituents results from a change in the affinity of these analogs for the .alpha.- and .beta.-adrenergic receptors. Tests were done on guinea pig atria, aortic strip and ileum, and on rat cerebral cortical slice.