Conjugates of catecholamines. 1. N-Alkyl-functionalized carboxylic acid congeners and amides related to isoproterenol

• Published in: Journal of medicinal chemistry Vol. 26; no. 4; pp. 492 - 499
• Main Authors: Jacobson, Kenneth A, Marr-Leisy, Debra, Rosenkranz, Roberto P, Verlander, Michael S, Melmon, Kenneth L, Goodman, Murray
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.04.1983
• Subjects: Animals; Catecholamines - chemical synthesis; Catecholamines - pharmacology; Cell Line; Cyclic AMP - metabolism; Isoproterenol - pharmacology; Methods
• ISSN: 0022-2623; 1520-4804
• 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.