.alpha.-Adrenergic agents. 1. Direct-acting .alpha.1 agonists related to methoxamine

Publisher Website
Google Scholar
Abstract
A series of phenylethylamines related to methoxamine was prepared and evaluated for direct .alpha.1-receptor agonist activity in rabbits. It observed that for open-chain compounds such as methoxamine, in which the amine-containing portion is free to adopt numerous conformations, a hydroxyl group is necessary for direct .alpha.1-adrenergic activity. When the hydroxyl is removed the direct component of activity is greatly reduced unless the amine is incorporated into a more sterically defined structure. For a phenylethylamine to be active as a direct .alpha.1-receptor agonist it should have a .beta.-N in a fully extended conformation relative to a substituted phenyl ring. For optimum potency, the N should be exocyclic to a saturated 6 membered ring. It may be further incorporated exocyclic or endocyclic into an additional ring so long as the amine occupies a well-defined region of space relative to the aromatic portion of a molecule. The ED50 values of some of the more potent compounds as .alpha.1-receptor agonists are on the order of 1 .times. 10-7M.
Keywords