Beta-adrenoreceptor antagonists with multiple pharmacophores: persistent inhibition of rat heart adenylate cyclase.

Abstract

beta-Adrenoreceptor antagonists containing several pharmacophores, so called alprenolol-Jeffamines, were studied. These compounds are derived from Jeffamine NH2-CH-(CH3)-CH2-[-O-CH2-CH(CH3)-]n-NH2, n = 2.6 ave. by substitution of nitrogen with 3-(2-allylphenoxy)-2-hydroxypropyl groups, which are part of the Alprenolol pharmacophore. Alprenolol-Jeffamines inhibited (-)isoprenaline stimulated adenylate cyclase activity; the derivative with one pharmacophore was about 4-fold and the derivative with two pharmacophores was about 17-fold less potent than (+/-)alprenolol; the trisubstituted derivative which has one complete and two partial pharmacophores was ineffective. The ratio of Ki's for inhibition of (-)3H-DHA binding and for inhibition of adenylate cyclase were approximately one for each derivative. When (+/-)alprenolol and alprenolol-Jeffamine derivatives were injected intraperitoneally into rats and heart membranes or homogenates were prepared 18-20 h afterwards, the mono, di, and trisubstituted derivatives, but not (+/-)alprenolol, inhibited binding of (-)3H-DHA. This persistency pattern is different from that observed in vitro, where only di and trisubstituted derivatives are persistent. Slow metabolism/slow excretion of the monosubstituted derivative may be a source of the increased persistency in vivo. In similarly prepared animals, the dose-response curve for (-)isoprenaline stimulated adenylate cyclase was shifted to the right 3-to-4 fold for mono and disubstituted derivatives but was unaffected by (+/-)alprenolol and the trisubstituted derivative. The results suggest that these derivatives interact with physiologically important beta-adrenoreceptors in vitro, and that, in vivo, they persistently block beta-adrenoreceptors and inhibit isoprenaline stimulated adenylate cyclase.