.beta.-Adrenergic antagonists with multiple pharmacophores: persistent blockade of receptors

Abstract

.beta.-Adrenergic antagonists containing from 1-4 identical pharmacophores were prepared and studied. These compounds had the general structure R2NCH(CH3)CH2[-OCH2CH(CH3)-]2-8NR2, where R is either H or an aryl-OCH2CHOHCH2 group. Synthesis was achieved by reaction of aryl glycidyl ethers with Jeffamines, which are primary diamines used in the manufacture of plastics. The following aryl groups were used: 2-allylphenyl; 4-(2-methoxyethyl)phenyl; 1-naphthyl; and 4-methoxyphenyl. The first 3 correspond to moieties of the established drugs alprenolol, metoprolol and propranolol, respectively. The affinities of these compounds for .beta.-adrenergic receptors of rat heart and lung were estimated by measuring their ability to compete with the specific binding of (-)-[3H]-dihydroalprenolol. Compounds containing 1 pharmacophore bound to the receptors with affinities comparable to those of the parent drugs and the blockade of receptors could be dissociated by successive washes as easily as were those of the parent drugs. Compounds containing 2 or 3 pharmacophores had somewhat lower affinities for receptors, but the resulting blockade was persistent even after successive washing.