α-Adrenergic Agents. 1. Direct-Acting α1 Agonists Related to Methoxamine

Article abstract of DOI:10.1021/jm00144a012

A series of phenylethylamines related to methoxamine has been prepared and evaluated for direct α₁-receptor agonist activity.It has been observed that for open-chain compounds such as methoxamine, in which the amine-containing portion is free to adopt numerous conformations, an hydroxyl group is necessary for direct α₁-adrenergic activity.When the hydroxyl is removed, however, the direct component of activity is greatly reduced unless the amine is incorporated into a more sterically defined structure.From our studies we have concluded that in order for a phenylethylamine to be active as a direct α₁-receptor agonist it should have a β nitrogen in a fully extended conformation relative to a substituted phenyl ring.For optimum potency, the nitrogen should be exocyclic to a saturated six-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 α₁-receptor agonists are on the order of 1 * 10^-7 M.