β-ADRENORECEPTOR ANTAGONISTS WITH MULTIPLE PHARMACOPHORES: PERSISTENT INHIBITION OF RAT HEART ADENYLATE CYCLASE

• 1 β-Adrenoreceptor antagonists containing several pharmacophores, so called alprenolol-Jeffamines, were studied. These compounds are derived from Jeffamine^R NH₂-CH-(CH₃)-CH₂-[-O-CH₂-CH(CH₃)-]_n- NH₂₉n = 2.6 ave. by substitution of nitrogen with 3-(2-allylphenoxy)-2-hydroxypropyl groups, which are part of the Alprenolol^R pharmacophore.
• 2 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.
• 3 The ratio of K_i's for inhibition of (-)³H-DHA binding and for inhibition of adenylate cyclase were approximately one for each derivative.
• 4 When (+)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 bindng 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.
• 5 In similarly prepared animals, the dose-response curve for (-)isoprenaiine 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.
• 6 The results suggest that these derivatives interact with physiologically important β-adrenoreceptors in vitro, and that, in vivo, they persistently block β-adrenoreceptors and inhibit isoprenaline stimulated adenylate cyclase.