Jacobson K A, Marr-Leisy D, Rosenkranz R P, Verlander M S, Melmon K L, Goodman M
J Med Chem. 1983 Apr;26(4):492-9. doi: 10.1021/jm00358a007.
A series of functionalized catecholamines (congeners) has been synthesized in which, formalistically, the N-isopropyl group of isoproterenol has been extended by a linear alkyl chain of varying length, terminated by a carboxy group or a substituted amide. The compounds were prepared generally via the reductive amination of norepinephrine with a keto acid or a preformed keto amide. An alternate synthesis of the model amide derivatives, involving activation of the carboxylic acid congeners and coupling with amines, was complicated in the case of short-chain derivatives by facile cyclization to lactams. In vitro evaluation of these compounds as potential beta-adrenergic agonists has shown that, while the carboxylic acid congeners have relatively low potencies, the model amide derivatives have potencies that are highly dependent on both the length of the alkyl chain and also the nature of the substituent on the amide. In general, aromatic amides are the most potent, although the nature and position of substituents on the aromatic group dramatically influences their potency. The implications of these studies, in terms of general beta-adrenergic drug design and also the attachment of the carboxylic acid congeners to carriers, are discussed.
已经合成了一系列官能化的儿茶酚胺（同系物），从形式上看，异丙肾上腺素的N - 异丙基已通过不同长度的直链烷基链进行了扩展，该烷基链以羧基或取代酰胺结尾。这些化合物一般通过去甲肾上腺素与酮酸或预先形成的酮酰胺的还原胺化反应来制备。模型酰胺衍生物的另一种合成方法，涉及羧酸同系物的活化以及与胺的偶联，对于短链衍生物而言，由于容易环化形成内酰胺而变得复杂。对这些化合物作为潜在β - 肾上腺素能激动剂的体外评估表明，虽然羧酸同系物的效力相对较低，但模型酰胺衍生物的效力高度依赖于烷基链的长度以及酰胺上取代基的性质。一般来说，芳香酰胺是最有效的，尽管芳香基团上取代基的性质和位置会极大地影响它们的效力。讨论了这些研究在一般β - 肾上腺素能药物设计以及羧酸同系物与载体连接方面的意义。
