Henri Demarne

Synthesis of indolyloxypropanolamines bearing the 2-(1H-indol-3yl)-1,1-dimethylethyl group: structure—activity studies and anti-hypertensive activity

Abstract New indolyloxypropanolamines in which the substituent at the side chain nitrogen atom was the 2-(1H- indol-3yl)-1,1-dimethylethyl group have been synthesized as putative anti-hypertensive agents. In vitro assays were used to measure their affinity for the β1-, β2, α1- and α2-adrenoceptors, where a marked tendency towards β2- adrenoceptor selectivity was observed. The tryptamine indole ring was responsible for their α1 and Ca2+ blocker properties and results compared to those obtained with the 4 stereoisomers of 1-((2-(1H-indol-3yl)-1 methylethyl)amino)-3-(2-methylphenoxy)-2 propanol 32. Intrinsic sympathomimetric activity (ISA) was imparted to the oxyindole ring. In the anesthetized dog, five analogs (4, 5, 24, 25, 27) antagonized the effects of isoproterenol (β-blockade) and norepinephrine (α-blockade) more than 50% at doses lower than or equal to 0.1 mg/kg i.v. The anti-hypertensive activity was confirmed in spontaneously hypertensive rats. Two compounds, 4 (CM 40441a) and 25 (SR 41717a), were selected for further pharmacological studies.