Synthesis and structure-activity relationships among .alpha.-adrenergic receptor agonists of the phenylethanolamine type

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Abstract
Nineteen arylethanolamine derivatives related to norepinephrine were prepared and tested for .alpha.-adrenergic stimulant activity [in isolated rat aorta]. In 1 series, the analogs have a p-hydroxy function, while the meta position is substituted by methyl, ethyl, isopropyl, cyclohexyl, fluoro, chloro, iodo, carboxy, carbomethoxy and methylsulfamido groups. The other series is meta hydroxylated with the para position substituted by the same groups. The influence of these groups on the .alpha.-adrenergic activity is discussed, and the compounds are compared to octopamine, normetanephrine, norepinephrine and norphenylephrine. The introduction of an isopropyl, cyclohexyl and fluoro group in the meta position of octopamine improves its affinity by 3, 5 and 6 times, respectively, but when these groups are introduced in the para position of norphenylephrine their effects are detrimental. The most active compound, .alpha.-(aminomethyl)(4-fluoro-3-hydroxyphenyl)methanol, had .apprx. 1/100 the affinity and the same intrinsic activity as norepinephrine.